Patent Publication Number: US-2021187088-A1

Title: Cancer vaccines for uterine cancer

Description:
FIELD OF THE INVENTION 
     The invention relates to the field of cancer, in particular uterine cancer. In particular, it relates to the field of immune system directed approaches for tumor reduction and control. Some aspects of the invention relate to vaccines, vaccinations and other means of stimulating an antigen specific immune response against a tumor in individuals. Such vaccines comprise neoantigens resulting from frameshift mutations that bring out-of-frame sequences of the ARID1A, KMT2B, KMT2D, PIK3R1, and PTEN genes in-frame. Such vaccines are also useful for ‘off the shelf’ use. 
     BACKGROUND OF THE INVENTION 
     There are a number of different existing cancer therapies, including ablation techniques (e.g., surgical procedures and radiation) and chemical techniques (e.g., pharmaceutical agents and antibodies), and various combinations of such techniques. Despite intensive research such therapies are still frequently associated with serious risk, adverse or toxic side effects, as well as varying efficacy. 
     There is a growing interest in cancer therapies that aim to target cancer cells with a patient&#39;s own immune system (such as cancer vaccines or checkpoint inhibitors, or T-cell based immunotherapy). Such therapies may indeed eliminate some of the known disadvantages of existing therapies, or be used in addition to the existing therapies for additional therapeutic effect. Cancer vaccines or immunogenic compositions intended to treat an existing cancer by strengthening the body&#39;s natural defenses against the cancer and based on tumor-specific neoantigens hold great promise as next-generation of personalized cancer immunotherapy. Evidence shows that such neoantigen-based vaccination can elicit T-cell responses and can cause tumor regression in patients. 
     Typically the immunogenic compositions/vaccines are composed of tumor antigens (antigenic peptides or nucleic acids encoding them) and may include immune stimulatory molecules like cytokines that work together to induce antigen-specific cytotoxic T-cells that target and destroy tumor cells. Vaccines containing tumor-specific and patient-specific neoantigens require the sequencing of the patients&#39; genome and tumor genome in order to determine whether the neoantigen is tumor specific, followed by the production of personalized compositions. Sequencing, identifying the patient&#39;s specific neoantigens and preparing such personalized compositions may require a substantial amount of time, time which may unfortunately not be available to the patient, given that for some tumors the average survival time after diagnosis is short, sometimes around a year or less. 
     Accordingly, there is a need for improved methods and compositions for providing subject-specific immunogenic compositions/cancer vaccines. In particular it would be desirable to have available a vaccine for use in the treatment of cancer, wherein such vaccine is suitable for treatment of a larger number of patients, and can thus be prepared in advance and provided off the shelf. There is a clear need in the art for personalized vaccines which induce an immune response to tumor specific neoantigens. One of the objects of the present disclosure is to provide personalized therapeutic cancer vaccines that can be provided off the shelf. An additional object of the present disclosure is to provide cancer vaccines that can be provided prophylactically. Such vaccines are especially useful for individuals that are at risk of developing cancer. 
     SUMMARY OF THE INVENTION 
     In one embodiment, the disclosure provides a vaccine for use in the treatment of uterine cancer, said vaccine comprising: 
     (i) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 530, an amino acid sequence having 90% identity to Sequence 530, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 530; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 531, an amino acid sequence having 90% identity to Sequence 531, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 531; preferably also comprising 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 532, an amino acid sequence having 90% identity to Sequence 532, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 532; 
     (ii) at least two peptides, wherein each peptide, or a collection of tiled peptides, comprises a different amino acid sequence selected from Sequences 1-5, an amino acid sequence having 90% identity to Sequences 1-5, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 1-5; 
     (iii) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 102, an amino acid sequence having 90% identity to Sequence 102, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 102; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 103, an amino acid sequence having 90% identity to Sequence 103, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 103; 
     (iv) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 218, an amino acid sequence having 90% identity to Sequence 218, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 218; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 219, an amino acid sequence having 90% identity to Sequence 219, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 219; preferably also comprising 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 220, an amino acid sequence having 90% identity to Sequence 220, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 220; 
     and/or 
     (v) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 473, an amino acid sequence having 90% identity to Sequence 473, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 473; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 474, an amino acid sequence having 90% identity to Sequence 474, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 474. 
     In one embodiment, the disclosure provides a collection of frameshift-mutation peptides comprising: 
     (i) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 530, an amino acid sequence having 90% identity to Sequence 530, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 530; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 531, an amino acid sequence having 90% identity to Sequence 531, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 531; preferably also comprising 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 532, an amino acid sequence having 90% identity to Sequence 532, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 532; 
     (ii) at least two peptides, wherein each peptide, or a collection of tiled peptides, comprises a different amino acid sequence selected from Sequences 1-5, an amino acid sequence having 90% identity to Sequences 1-5, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 1-5; 
     (iii) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 102, an amino acid sequence having 90% identity to Sequence 102, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 102; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 103, an amino acid sequence having 90% identity to Sequence 103, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 103; 
     (iv) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 218, an amino acid sequence having 90% identity to Sequence 218, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 218; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 219, an amino acid sequence having 90% identity to Sequence 219, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 219; preferably also comprising 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 220, an amino acid sequence having 90% identity to Sequence 220, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 220; 
     and/or 
     (v) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 473, an amino acid sequence having 90% identity to Sequence 473, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 473; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 474, an amino acid sequence having 90% identity to Sequence 474, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 474. 
     In one embodiment, the disclosure provides a peptide comprising an amino acid sequence selected from the groups: 
     (i) Sequences 530-560, an amino acid sequence having 90% identity to Sequences 530-560, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 530-560 
     (ii) Sequences 1-101, an amino acid sequence having 90% identity to Sequences 1-101, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 1-101; 
     (iii) Sequences 102-217, an amino acid sequence having 90% identity to Sequences 102-217, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 102-217; 
     (iv) Sequences 218-472, an amino acid sequence having 90% identity to Sequences 218-472, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 218-472; 
     (v) Sequences 473-529, an amino acid sequence having 90% identity to Sequences 473-529, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 473-529. 
     Preferably the peptide is Sequence 7, an amino acid sequence having 90% identity to Sequence 7, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 7; or a collection comprising said peptide. 
     Preferably the peptide is Sequence 103, an amino acid sequence having 90% identity to Sequence 103, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 103; or a collection comprising said peptide. 
     Preferably the peptide is Sequence 474, an amino acid sequence having 90% identity to Sequence 474, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 474; or a collection comprising said peptide. 
     Preferably the peptide is Sequence 534 or 535 , an amino acid sequence having 90% identity to Sequence 534 or 535, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 534 or 535; or a collection comprising said peptide. 
     In some embodiments of the disclosure, the peptides are linked, preferably wherein said peptides are comprised within the same polypeptide. 
     In one embodiment, the disclosure provides one more isolated nucleic acid molecules encoding the peptides or collection of peptides as disclosed herein. In one embodiment, the disclosure provides one or more vectors comprising the nucleic acid molecules disclosed herein, preferably wherein the vector is a viral vector. In one embodiment, the disclosure provides a host cell comprising the isolated nucleic acid molecules or the vectors as disclosed herein. 
     In one embodiment, the disclosure provides a binding molecule or a collection of binding molecules that bind the peptide or collection of peptides disclosed herein, where in the binding molecule is an antibody, a T-cell receptor, or an antigen binding fragment thereof. 
     In one embodiment, the disclosure provides a chimeric antigen receptor or collection of chimeric antigen receptors each comprising i) a T cell activation molecule; ii) a transmembrane region; and iii) an antigen recognition moiety; wherein said antigen recognition moieties bind the peptide or collection of peptides disclosed herein. In one embodiment, the disclosure provides a host cell or combination of host cells that express the binding molecule or collection of binding molecules, or the chimeric antigen receptor or collection of chimeric antigen receptors as disclosed herein. 
     In one embodiment, the disclosure provides a vaccine comprising the peptide or collection of peptides, the nucleic acid molecules, the vectors, or the host cells as disclosed herein; and a pharmaceutically acceptable excipient and/or adjuvant, preferably an immune-effective amount of adjuvant. 
     In one embodiment, the disclosure provides the vaccines or collection of vaccines as disclosed herein for use in the treatment of uterine cancer in an individual. In one embodiment, the disclosure provides the vaccines as disclosed herein for prophylactic use in the prevention of uterine cancer in an individual. In one embodiment, the disclosure provides the vaccines as disclosed herein for use in the preparation of a medicament for treatment of uterine cancer in an individual or for prophylactic use. In one embodiment, the disclosure provides methods of treating an individual for uterine cancer or reducing the risk of developing said cancer, the method comprising administering to the individual in need thereof a therapeutically effective amount of a vaccine as disclosed herein. In some embodiments, the individual prophylactically administered a vaccine as disclosed herein has not been diagnosed with uterine cancer. For example, for around 5% of uterine endometrial cancers, a genetic predisposition contributes to the development of cancer. These individuals often have Lynch syndrome, characterized by germline mutations in mismatch repair genes, such as MLH1, MSH2, MLH3, MSH6, and PMS1, PMS2, TGFBR2, or the EPCAM gene. 
     In one embodiment, the individual has uterine cancer and one or more cancer cells of the individual: 
     (i) expresses a peptide having the amino acid sequence selected from Sequences 1-560, an amino acid sequence having 90% identity to any one of Sequences 1-560, or a fragment thereof comprising at least 10 consecutive amino acids of amino acid sequence selected from Sequences 1-560; 
     (ii) or comprises a DNA or RNA sequence encoding an amino acid sequences of (i). 
     In one embodiment, the disclosure provides a method of stimulating the proliferation of human T-cells, comprising contacting said T-cells with the peptide or collection of peptides, the nucleic acid molecules, the vectors, the host cell, or the vaccine as disclosed herein. 
     In one embodiment, the disclosure provides a storage facility for storing vaccines. Preferably the facility stores at least two different cancer vaccines as disclosed herein. Preferably the storing facility stores a vaccine comprising: 
     (i) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 530, an amino acid sequence having 90% identity to Sequence 530, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 530; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 531, an amino acid sequence having 90% identity to Sequence 531, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 531; preferably also comprising 
     a peptide, or a collection of tiled peptides, having the amino acid sequence pselected from Sequence 532, an amino acid sequence having 90% identity to Sequence 532, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 532; 
     and one or more vaccines selected from: 
     a vaccine comprising: 
     (ii) at least two peptides, wherein each peptide, or a collection of tiled peptides, comprises a different amino acid sequence selected from Sequences 1-5, an amino acid sequence having 90% identity to Sequences 1-5, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 1-5; 
     (iii) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 102, an amino acid sequence having 90% identity to Sequence 102, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 102; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 103, an amino acid sequence having 90% identity to Sequence 103, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 103; 
     a vaccine comprising: 
     (iv) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 218, an amino acid sequence having 90% identity to Sequence 218, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 218; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 219, an amino acid sequence having 90% identity to Sequence 219, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 219; preferably also comprising 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 220, an amino acid sequence having 90% identity to Sequence 220, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 220; and/or 
     a vaccine comprising: 
     (v) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 473, an amino acid sequence having 90% identity to Sequence 473, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 473; and 
     a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 474, an amino acid sequence having 90% identity to Sequence 474, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 474. 
     In one embodiment, the disclosure provides a method for providing a vaccine for immunizing a patient against a cancer in said patient comprising determining the sequence of ARID1A, KMT2B, KMT2D, PIK3R1, and/or PTEN in cancer cells of said cancer and when the determined sequence comprises a frameshift mutation that produces a neoantigen of Sequence 1-560 or a fragment thereof, providing a vaccine comprising said neoantigen or a fragment thereof. Preferably, the vaccine is obtained from a storage facility as disclosed herein. 
     REFERENCE TO A SEQUENCE LISTING 
     The Sequence listing, which is a part of the present disclosure, includes a text file comprising amino acid and/or nucleic acid sequences. The subject matter of the Sequence listing is incorporated herein by reference in its entirety. The information recorded in computer readable form is identical to the written sequence listing. In the event of a discrepancy between the Sequence listing and the description, e.g., in regard to a sequence or sequence numbering, the description (e.g., Table 1) is leading. 
     DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENTS 
     One issue that may arise when considering personalized cancer vaccines is that once a tumor from a patient has been analysed (e.g. by whole genome or exome sequencing), neoantigens need to be selected and made in a vaccine. This may be a time consuming process, while time is something the cancer patient usually lacks as the disease progresses. 
     Somatic mutations in cancer can result in neoantigens against which patients can be vaccinated. Unfortunately, the quest for tumor specific neoantigens has yielded no targets that are common to all tumors, yet foreign to healthy cells. Single base pair substitutions (SNVs) at best can alter 1 amino acid which can result in a neoantigen. However, with the exception of rare site-specific oncogenic driver mutations (such as RAS or BRAF) such mutations are private and thus not generalizable. 
     An “off-the-shelf” solution, where vaccines are available against each potential-neoantigen would be beneficial. The present disclosure is based on the surprising finding that, despite the fact that there are infinite possibilities for frame shift mutations in the human genome, a vaccine can be developed that targets the novel amino acid sequence following a frame shift mutation in a tumor with potential use in a large population of cancer patients. 
     Neoantigens resulting from frame shift mutations have been previously described as potential cancer vaccines. See, for example, WO95/32731, WO2016172722 (Nantomics), WO2016/187508 (Broad), WO2017/173321 (Neon Therapeutics), US2018340944 (University of Connecticut), and WO2019/012082 (Nouscom), as well as Rahma et al. (Journal of Translational Medicine 2010 8:8) which describes peptides resulting from frame shift mutations in the von Hippel-Lindau tumor suppressor gene (VHL) and Rajasagi et al. (Blood 2014 124(3):453-462) which reports the systematic identification of personal tumor specific neoantigens. 
     The present disclosure provides a unique set of sequences resulting from frame shift mutations and that are shared among uterine cancer patients. The finding of shared frame shift sequences is used to define an off-the-shelf uterine cancer vaccine that can be used for both therapeutic and prophylactic use in a large number of individuals. 
     In the present disclosure we provide a source of common neoantigens induced by frame shift mutations, based on analysis of 530 TCGA uterine tumor samples and 56 uterine tumor samples from other resources (see Priestley et al. 2019 at https://doi.org/10.1101/415133). We find that these frame shift mutations can produce long neoantigens. These neoantigens are typically new to the body, and can be highly immunogenic. The heterogeneity in the mutations that are found in tumors of different organs or tumors from a single organ in different individuals has always hampered the development of specific medicaments directed towards such mutations. The number of possible different tumorigenic mutations, even in a single gene as P53 was regarded prohibitive for the development of specific treatments. In the present disclosure it was found that many of the possible different frame shift mutations in a gene converge to the same small set of 3′ neo open reading frame peptides (neopeptides or NOPs). We find a fixed set of only 1,244 neopeptides in as much as 30% of all TCGA cancer patients. For some tumor classes this is higher; e.g. for colon and cervical cancer, peptides derived from only ten genes (saturated at 90 peptides) can be applied to 39% of all patients. 50% of all TCGA patients can be targeted at saturation (using all those peptides in the library found more than once). A pre-fabricated library of vaccines (peptide, RNA or DNA) based on this set can provide off the shelf, quality certified, ‘personalized’ vaccines within hours, saving months of vaccine preparation. This is important for critically ill cancer patients with short average survival expectancy after diagnosis. 
     The concept of utilizing the immune system to battle cancer is very attractive and studied extensively. Indeed, neoantigens can result from somatic mutations, against which patients can be vaccinated 1 - 11 . Recent evidence suggests that frame shift mutations, that result in peptides which are completely new to the body, can be highly immunogenic 12 - 15 . The immune response to neoantigen vaccination, including the possible predictive value of epitope selection has been studied in great detail 8 ,  13 ,  16 - 21  and WO2007/101227, and there is no doubt about the promise of neoantigen-directed immunotherapy. Some approaches find subject-specific neoantigens based on alternative reading frames caused by errors in translation/transcription (WO2004/111075). Others identify subject specific neoantigens based on mutational analysis of the subjects tumor that is to be treated (WO1999/058552; WO2011/143656; US20140170178; WO2016/187508; WO2017/173321). The quest for common antigens, however, has been disappointing, since virtually all mutations are private. For SNV-derived amino acid changes, one can derive algorithms that predict likely good epitopes, but still every case is different. 
     A change of one amino acid in an otherwise wild-type protein may or may not be immunogenic. The antigenicity depends on a number of factors including the degree of fit of the proteasome-produced peptides in the MHC and ultimately on the repertoire of the finite T-cell system of the patient. In regards to both of these points, novel peptide sequences resulting from a frame shift mutation (referred to herein as novel open reading frames or pNOPs) are a priori expected to score much higher. For example, a fifty amino acid long novel open reading frame sequence is as foreign to the body as a viral antigen. In addition, novel open reading frames can be processed by the proteasome in many ways, thus increasing the chance of producing peptides that bind MHC molecules, and increasing the number of epitopes will be seen by T-cell in the body repertoire. 
     It is has been established that novel proteins/peptides can arise from frameshift mutations 32,36 . Furthermore, tumors with a high load of frameshift mutations (micro-satellite instable tumors) have a high density of tumor infiltrating CD8+ T cells 33 . In fact, it has been shown that neo-antigens derived from frameshift mutations can elicit cytotoxic T cell responses 32,34,33 . A recent study demonstrated that a high load of frameshift indels or other mutation types correlates with response to checkpoint inhibitors 35 . 
     Binding affinity to MHC class-I molecules was systematically predicted for frameshift indel and point mutations derived neoantigens 35 .Based on this analysis, neoantigens derived from frameshifts indels result in 3 times more high-affinity MHC binders compared to point mutation derived neoantigens, consistent with earlier work 31 . Almost all frameshift derived neoantigens are so-called mutant-specific binders, which means that cells with reactive T cell receptors for those frameshift neoantigens are (likely) not cleared by immune tolerance mechanisms 35 . These data are all in favour of neo-peptides from frameshift being superior antigens. 
     Here we report that frame shift mutations, which are also mostly unique among patients and tumors, nevertheless converge to neo open reading frame peptides (NOPs) from their translation products that surprisingly result in common neoantigens in large groups of cancer patients. The disclosure is based, in part, on the identification of common, tumor specific novel open reading frames resulting from frame shift mutations. Accordingly, the present disclosure provides novel tumor neoantigens and vaccines for the treatment of cancer. In some embodiments, multiple neoantigens corresponding to multiple NOPs can be combined, preferably within a single peptide or a nucleic acid molecule encoding such single peptide. This has the advantage that a large percentage of the patients can be treated with a single vaccine. 
     While not wishing to be bound by theory, the surprisingly high number of frame shift induced novel open reading frames shared by cancer patients can be explained, at least in part, as follows. Firstly, on the molecular level, different frame shift mutations can lead to the generation of shared novel open reading frames (or sharing at least part of a novel open reading frame). Secondly, the data presented herein suggests that frame shift mutations are strong loss-of-function mutations. This is illustrated in  FIG. 2A , where it can be seen that the SNVs in the TCGA database are clustered within the p53 gene, presumably because mutations elsewhere in the gene do not inactive gene function. In contrast, frame shift mutations occur throughout the p53 gene ( FIG. 2B ). This suggests that frame shift mutations virtually anywhere in the p53 ORF reduce function (splice variants possibly excluded), while not all point mutations in p53 are expected to reduce function. Finally, the process of tumorigenesis naturally selects for loss of function mutations in genes that may suppress tumorigenesis. Interestingly, the present disclosure identifies frame shift mutations in genes that were not previously known as classic tumor suppressors, or that apparently do so only in some tissue tumor types (see, e.g.,  FIG. 8 ). These three factors are likely to contribute to the surprisingly high number of frame shift induced novel open reading frames shared by cancer patients; in particular, while frame shift mutations generally represent less than 10% of the mutations in cancer cells, their contribution to neoantigens and potential as vaccines is much higher. The high immunogenic potential of peptides resulting from frameshifts is to a large part attributable to their unique sequence, which is not part of any native protein sequence in humans, and would therefore not be recognised as ‘self’ by the immune system, which would lead to immune tolerance effects. The high immunogenic potential of out-of-frame peptides has been demonstrated in several recent papers. 
     Neoantigens are antigens that have at least one alteration that makes them distinct from the corresponding wild-type, parental antigen, e.g., via mutation in a tumor cell. A neoantigen can include a polypeptide sequence or a nucleotide sequence 
     As used herein the term “ORF” refers to an open reading frame. As used herein the term “neoORF” is a tumor-specific ORF (i.e., neoantigen) arising from a frame shift mutation. Peptides arising from such neo ORFs are also referred to herein as neo open reading frame peptides (NOPs) and neoantigens. 
     A “frame shift mutation” is a mutation causing a change in the frame of the protein, for example as the consequence of an insertion or deletion mutation (other than insertion or deletion of 3 nucleotides, or multitudes thereof). Such frameshift mutations result in new amino acid sequences in the C-terminal part of the protein. These new amino acid sequences generally do not exist in the absence of the frameshift mutation and thus only exist in cells having the mutation (e.g., in tumor cells and pre-malignant progenitor cells). 
       FIGS. 3 and 4  indicate how many cancer patients exhibit in their tumor a frame shift in region x or gene y of the genome. The patterns result from the summation of all cancer patients. The disclosure surprisingly demonstrates that within a single cancer type (i.e. uterine cancer), the fraction of patients with a frame shift in a subset of genes is much higher than the fractions identified when looking at all cancer patients. We find that careful analysis of the data shows that frame shift mutations in only five genes together are found in at least 30% of all uterine cancers. 
     Novel 3′ neo open reading frame peptides (i.e., NOPs) of ARID1A, PTEN, KMT2D, KMT2B, and PIK2R1 are depicted in table 1. The NOPs, are defined as the amino acid sequences encoded by the longest neo open reading frame sequence identified. Sequences of these NOPs are represented in table 1 as follows: 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Library of NOP sequences 
               
               
                 Sequences of NOPs including the percentage of uterine cancer patients 
               
               
                 identified in the present study with each NOP. 
               
               
                 The sequences referred to herein correspond to the sequence numbering in the table below. 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 % 
               
               
                   
                   
                   
                   
                 uterine 
               
               
                   
                   
                   
                   
                 cancer 
               
               
                 Sequence 
                 PeptideID 
                 gene 
                 PeptideSeq 
                 patients 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 pNOP43369 
                 ARID1A 
                 TNQALPKIEVICRGTPRCPSTVPPSPAQPYLRVSLPEDRYTQAWAPTSRTPWGAMVPRGVSMAHKVA 
                 2.26 
               
               
                   
                   
                   
                 TPGSQTIMPCPMPTTPVQAWLEA 
                   
               
               
                   
                   
                   
                 ALGPHSRISCLPTQTRGCILLAATPRSSSSSSSNDMIPMAISSPPKAPLLAAPSPASRLQCINSNSRI 
                   
               
               
                   
                   
                   
                 TSGQWMAHMALLPSGTKGRCTACHTALGRGSLSSSSCPQPSPSLPASNKLPSLPLSKMYTTSMAMPIL 
                   
               
               
                   
                   
                   
                 PLPQ 
                   
               
               
                   
               
               
                 2 
                 pNOP6110 
                 ARID1A 
                 LLLSADQQAAPRTNFHSSLAETVSLHPLAPMPSKTCHHK 
                 2.26 
               
               
                   
               
               
                 3 
                 pNOP82315 
                 ARID1A 
                 RSYRRMIHLWWTAQISLGVCRSLTVACCTGGLVGGTPLSISRPTSRARQSCCLPGLTHPAHQPLGSM 
                 2.26 
               
               
                   
                   
                   
                 PCRAGRRVPWAASLIHSRFLLMDNKAPAGMVNRARLHITTSKVLTLSSSSHPTPSNHRPRPLMPNLR 
                   
               
               
                   
                   
                   
                 ISSSHSLNHHSSSPLSLHTPSSHPSLHISSPRLHIPPSSRRHSSTPRASPPTHSHRLSLLTSSSNLS 
                   
               
               
                   
                   
                   
                 SQHPRRSP 
                   
               
               
                   
               
               
                 4 
                 pNOP5538 
                 ARID1A 
                 SRLRILSPSLSSPSKLPIPSSASLHRRSYLKIHLGLRHPQPPQ 
                 2.08 
               
               
                   
               
               
                 5 
                 pNOP88606 
                 ARID1A 
                 FWPHPPSAAWRSCIALWCASSVTERTRCAGRWLWYCWPTWLRGTAWQLVPLQCRRAVSATSWAS 
                 1.89 
               
               
                   
               
               
                 6 
                 pNOP323677 
                 ARID1A 
                 LRSTRTKNGGNLQPTSMWAHQAVLPAP 
                 1.32 
               
               
                   
                   
                   
                 SSSVSFLSSYLPSPAWHPRPFPVPCWLSRQCCSVSLRTTLACCSARQPDATSATQWPVGQHHASFHEPI 
                   
               
               
                   
                   
                   
                 KHCPRSRLYAEEPPDAPVQFPPARLSLISASAFRRTDTHRHGLLPAELHGELWSPGGSVWPTRWLPQA 
                   
               
               
                   
               
               
                 7 
                 pNOP13360 
                 ARID1A 
                 AKL 
                 1.13 
               
               
                   
                   
                   
                 PILAATGTSVRTAARTWVPRAAIRVPDPAAVPDDHAGPGAECHGRPLLYTADSSLWTTRPQRVWSTG 
                   
               
               
                   
                   
                   
                 PDSILQPAKSSPSAAAATLLPATTVPDPSCPTFVSAAATVSTTTAPVLSASILPAAIPASTSAVPGSI 
                   
               
               
                   
                   
                   
                 PLPAVDDTAAPPEPAPLLTATGSVSLPAAATSAASTLDALPAGCVSSAPVSAVPANCLFPAALPSTAG 
                   
               
               
                   
                   
                   
                 AISRFIW 
                   
               
               
                   
               
               
                 8 
                 pNOP3000 
                 ARID1A 
                 VSGILSPLNDLQ 
                 1.13 
               
               
                   
                   
                   
                 ALGPHSRISCLPTQTRGCILLAATPRSSSSSSSNDMIPMAISSPPKAPLLAAPSPASRLQCINSNSRY 
                   
               
               
                   
                   
                   
                 PALL 
                   
               
               
                   
               
               
                 9 
                 pNOP39264 
                 ARID1A 
                 PCPGQWRTAPLLASLHSCTLG 
                 1.13 
               
               
                   
               
               
                 10 
                 pNOP81513 
                 ARID1A 
                 KSSISSVSMPLNARLNGEKTLPQTSLQLLIPRSPSPRSSLPLLRDQDLCRGPRLPSQPAVPWQKEET 
                 0.94 
               
               
                   
               
               
                 11 
                 pNOP57388 
                 ARID1A 
                 AHQGFPAAKESRVIQLSLLSLLIPPLTCLASEALPRPLLALPPVLLSLAQDHSRLLQCQATRCHLGHP 
                 0.57 
               
               
                   
                   
                   
                 VASRTASCILP 
                   
               
               
                   
               
               
                 12 
                 pNOP109934 
                 ARID1A 
                 ETSGPLSPLCVCEGDWWIDSGQQEQKMAGTCNQPQCGHIKQCCQLLEKAVYPVSLCL 
                 0.38 
               
               
                   
               
               
                 13 
                 pNOP141882 
                 ARID1A 
                 CGHDAAGCPRAACLGQGGREPLRVYSVRITAVGHLGITVDELIGFTSHL 
                 0.38 
               
               
                   
               
               
                 14 
                 pNOP171474 
                 ARID1A 
                 QVSIPALWDENAEGRSPSTCLAHSTCPCAAPHDSAGYHLPTWLC 
                 0.38 
               
               
                   
               
               
                 15 
                 pNOP232518 
                 ARID1A 
                 CGGLPARCLPWPRWTRTTQSLLCTNHGCWTSRYHR 
                 0.38 
               
               
                   
               
               
                 16 
                 pNOP266437 
                 ARID1A 
                 PRMELRVQRPSRRAASFHLALAQHRATGTSRS 
                 0.38 
               
               
                   
                   
                   
                 FLWQSVLHPRHPFWQPLPQPADYNVSTATAELQAANGWHIWPSCQAARRGDVQRAIQHWAGAAS 
                   
               
               
                   
               
               
                 17 
                 pNOP28543 
                 ARID1A 
                 AAAVAPSPAPACQPATSCPAFPSARCIQPVWQCLSCHCHSCY 
                 0.38 
               
               
                   
               
               
                 18 
                 pNOP289760 
                 ARID1A 
                 RTALPPHSSSRARPASSTCRTHPLSQLVWT 
                 0.38 
               
               
                   
               
               
                 19 
                 pNOP382230 
                 ARID1A 
                 LCQQAEHGLCPPGPRLSWREPNR 
                 0.38 
               
               
                   
                   
                   
                 AATKWSGGGTAWRCSGKTPWLHSPTSRGSWTYLHTPRAFACLSWTDSYTGQFALQLKPRTPFPPWA 
                   
               
               
                   
               
               
                 20 
                 pNOP40276 
                 ARID1A 
                 PMPSFPRRDWSWKPSANSASRTTMWT 
                 0.38 
               
               
                   
               
               
                 21 
                 pNOP578746 
                 ARID1A 
                 PLPPAAAAAAAATT 
                 0.38 
               
               
                   
                   
                   
                 YGWHDQPSGTPIFHGWNHGQQFCRDGSQPRDDGPWGCKVNSSHQNEQQGRWDTQDRIQIQEIQ 
                   
               
               
                   
               
               
                 22 
                 pNOP78127 
                 ARID1A 
                 FFYYNQ 
                 0.38 
               
               
                   
               
               
                 23 
                 pNOP91542 
                 ARID1A 
                 HGQYATSGWVRDVSPTRGHEPENPRNCCRHACCCQLYPKQAARLPQYESRGHDGNWTSLWTRD 
                 0.38 
               
               
                   
               
               
                 24 
                 pNOP108335 
                 ARID1A 
                 RTNPTVRMRPHCVPFWTGRILLPSAASVCPIPFEACHLCQAMTLRCPNTQGCCSSWAS 
                 0.19 
               
               
                   
               
               
                 25 
                 pNOP115908 
                 ARID1A 
                 TTRQMGHPRQNPNPRNPVLLLQPMRRSPSCMSWVVSLRGRCGWTVIWPSLRRRPWA 
                 0.19 
               
               
                   
               
               
                 26 
                 pNOP140600 
                 ARID1A 
                 SPGPLFHPGPQCRPFPAETGLGNPQQTQHPGQQCGPDSGHTPLQPPGEVV 
                 0.19 
               
               
                   
               
               
                 27 
                 pNOP160041 
                 ARID1A 
                 QGPLHLTTSPHQACRITFLRYPALLPCPGQWRTAPLLASLHSCTLG 
                 0.19 
               
               
                   
               
               
                 28 
                 pNOP205126 
                 ARID1A 
                 QQQRVHQGQQTRRGPHLMDLQKNGSQPLWMTCCLLGLAP 
                 0.19 
               
               
                   
               
               
                 29 
                 pNOP271959 
                 ARID1A 
                 DVQTPRAAAHPGQADPAAPQAPRTEAGTTNL 
                 0.19 
               
               
                   
               
               
                 30 
                 pNOP280686 
                 ARID1A 
                 VTPPWATGLMALTWPICHLRLGQGCVPHQGA 
                 0.19 
               
               
                   
               
               
                 31 
                 pNOP286473 
                 ARID1A 
                 LPAPTKHAESHSSGIQPCSPAPANGEPHLS 
                 0.19 
               
               
                   
               
               
                 32 
                 pNOP342491 
                 ARID1A 
                 STLRDPHIPWVEPWPTILQGWQPAQR 
                 0.19 
               
               
                   
               
               
                 33 
                 pNOP471545 
                 ARID1A 
                 FGGISPSHLALLKPHSLC 
                 0.19 
               
               
                   
               
               
                 34 
                 pNOP472965 
                 ARID1A 
                 GRARRYEPEPSVKTLQLA 
                 0.19 
               
               
                   
               
               
                 35 
                 pNOP525902 
                 ARID1A 
                 PFQARTSQLQRIVRRS 
                 0.19 
               
               
                   
               
               
                 36 
                 pNOP120573 
                 ARID1A 
                 CLAQCQLPQCRHGWRHKPHGCRRSNAWTAWHPTLWHTPSREDESRLHGQPALWP 
                 &lt;0.1 
               
               
                   
                   
                   
                 PHGAARRRRWRQQRWGGGASSLSRGRLAAPSLRLRATLRPEPVCRRRRRGRRLPPTTWRTTKPWPG 
                   
               
               
                   
                   
                   
                 SAAERRRRGPGALRGAPAELSRPRLPQPPVQLLLPQPQRLPPARPGLRAELPERWHSGLRRGGGCRLQ 
                   
               
               
                   
                   
                   
                 AASLLQRLRLLVVFVLRSAALRGHGGRRPLRGRRGNSPAHRHPHPQPTAHVAQLGPGLPGLPRGRLQ 
                   
               
               
                   
                   
                   
                 WRAPGRGRRQGPGGHGLAVLGGCGGGSCGGGRLGRGPTKEPPRAHEPREQRRRGAAARPDPSAIQ 
                   
               
               
                   
               
               
                 37 
                 pNOP1299 
                 ARID1A 
                 SNGSDGQDETSAIWRD 
                 &lt;0.1 
               
               
                   
               
               
                 38 
                 pNOP144966 
                 ARID1A 
                 RQPPGRKARAPPWGRRSRWERSCRTGPRAMGVAAAAEPAAAAGPARSRT 
                 &lt;0.1 
               
               
                   
               
               
                 39 
                 pNOP145255 
                 ARID1A 
                 SHTACVEAEEAAHNERHWNPGGMAGNDVPQVWSPGREHMGIRYHQHPAV 
                 &lt;0.1 
               
               
                   
               
               
                 40 
                 pNOP152466 
                 ARID1A 
                 FLWQSVLHPRHPFWQPLPQPADYNVSTATAGIQPCSPAPANGEPHLS 
                 &lt;0.1 
               
               
                   
               
               
                 41 
                 pNOP157058 
                 ARID1A 
                 AYPDPLREQDRAAAFPASRTLPTSPSEACDNSRGYTRDNRPGGAPT 
                 &lt;0.1 
               
               
                   
               
               
                 42 
                 pNOP162214 
                 ARID1A 
                 APTSRRPPEPISIPVWPRPCLCTPWHQCPAKHATTNDGRPHTGIS 
                 &lt;0.1 
               
               
                   
                   
                   
                 APREVALRAPARRRLPAPSRLPPPAPPPPRRLRPSLSSASGPWGEAAPPRPAGELPSPPPPPPSTNCS 
                   
               
               
                   
                   
                   
                 RR 
                   
               
               
                   
               
               
                 43 
                 pNOP16341 
                 ARID1A 
                 PARPGATRATPGATTVAGPRTGAPARARRTWPRSVGGLRRRQLRRRPPREGPNKGATTRP 
                 &lt;0.1 
               
               
                   
               
               
                 44 
                 pNOP187097 
                 ARID1A 
                 DLSHMAGLTHTRSNRDLRQDRSKDMGTQGSHTGPRPRSGTR 
                 &lt;0.1 
               
               
                   
               
               
                 45 
                 pNOP204073 
                 ARID1A 
                 NAAHRSEGQPRRLVAFPWHTPAPIWSLCPCAPHDKAPSI 
                 &lt;0.1 
               
               
                   
               
               
                 46 
                 pNOP221454 
                 ARID1A 
                 RSMRWVTQDRERYWILGGSARCLVQLPWRVGKKKKNF 
                 &lt;0.1 
               
               
                   
               
               
                 47 
                 pNOP222331 
                 ARID1A 
                 TEQMKCCTQIRGPTTKARGLPMAHASPHMVPLPLCPP 
                 &lt;0.1 
               
               
                   
                   
                   
                 TITSRSRPAAAVAAAAMGWGRLLTQPRPPCRPQPTASGNPTAGARLPSPPPRPPSSTNNMADNKALA 
                   
               
               
                   
               
               
                 48 
                 pNOP22341 
                 ARID1A 
                 WQRCRAAAAGAWSPTRGPSRTLTTTASPTTSTTPTTPTAAPTPRPPRPTR 
                 &lt;0.1 
               
               
                   
               
               
                 49 
                 pNOP251638 
                 ARID1A 
                 DPTVYPSGLAGFSCQALRLCVQYHSKPVICARQ 
                 &lt;0.1 
               
               
                   
                   
                   
                 HGRAGRPRRRQQPGQPAAAAALGAEESRAAAAGGGGGRGGGGGSGRARGNEGSRRAGKRGPRRG 
                   
               
               
                   
               
               
                 50 
                 pNOP26533 
                 ARID1A 
                 AAAAAGKGAAGRGREQWGWRRRRSRQRRRARRGAGPEELERERGP 
                 &lt;0.1 
               
               
                   
               
               
                 51 
                 pNOP272985 
                 ARID1A 
                 GKLQGVIPSCPQGRAPTAGWVTPTVVLPALG 
                 &lt;0.1 
               
               
                   
                   
                   
                 CTVFDWPVMTAVGHLPPPCVCACVENLETDCCPLFMQNHLRIQFTLCCPASPLGKSLSCFSLLLPPPLP 
                   
               
               
                   
               
               
                 52 
                 pNOP28463 
                 ARID1A 
                 PSPHAFLFLVLTLLPSGPYPTLFEKTKLCLHRRLFLF 
                 &lt;0.1 
               
               
                   
               
               
                 53 
                 pNOP317526 
                 ARID1A 
                 APGAAAAGGSRSPGPLSHPVQWIRWAR 
                 &lt;0.1 
               
               
                   
               
               
                 54 
                 pNOP325333 
                 ARID1A 
                 PLQSCCRPWARKCGDGTTTALSLWRSL 
                 &lt;0.1 
               
               
                   
               
               
                 55 
                 pNOP326245 
                 ARID1A 
                 QQHHDLQPQSAPRVARAPCRIFPTMPD 
                 &lt;0.1 
               
               
                   
               
               
                 56 
                 pNOP329083 
                 ARID1A 
                 TGKPKKLLSPCMLLPTLSKTGRQATPI 
                 &lt;0.1 
               
               
                   
               
               
                 57 
                 pNOP339133 
                 ARID1A 
                 PPHGDRRSSESWSEHIRDFQQPRRAE 
                 &lt;0.1 
               
               
                   
               
               
                 58 
                 pNOP345053 
                 ARID1A 
                 AGAIQLGSRMPLMMEVTPHSRSGIP 
                 &lt;0.1 
               
               
                   
               
               
                 59 
                 pNOP355250 
                 ARID1A 
                 RKPSSSSGRRRGARRRRRQRPSAGK 
                 &lt;0.1 
               
               
                   
               
               
                 60 
                 pNOP357957 
                 ARID1A 
                 TPWVPEVKCMDSLASHLMAHSLQGG 
                 &lt;0.1 
               
               
                   
               
               
                 61 
                 pNOP363287 
                 ARID1A 
                 GKHEHWGPTAESHAFQPRLGDVFS 
                 &lt;0.1 
               
               
                   
               
               
                 62 
                 pNOP366177 
                 ARID1A 
                 LASHDSRGTPPPPVCVCVCGELRN 
                 &lt;0.1 
               
               
                   
               
               
                 63 
                 pNOP390796 
                 ARID1A 
                 WAAPYRHQLRLLSKAPCGRGVMT 
                 &lt;0.1 
               
               
                   
               
               
                 64 
                 pNOP391130 
                 ARID1A 
                 WPRRSPPPPPAAWATRRRRRPRS 
                 &lt;0.1 
               
               
                   
               
               
                 65 
                 pNOP399373 
                 ARID1A 
                 LHIPEAEFHDSKPWVSAQYEYL 
                 &lt;0.1 
               
               
                   
               
               
                 66 
                 pNOP419746 
                 ARID1A 
                 PIIMPTGRARALPPRAPPIMA 
                 &lt;0.1 
               
               
                   
               
               
                 67 
                 pNOP450666 
                 ARID1A 
                 EMWRWDHDSTIPMEVLMTE 
                 &lt;0.1 
               
               
                   
               
               
                 68 
                 pNOP460168 
                 ARID1A 
                 QICLLWVGNLWTSIASMCL 
                 &lt;0.1 
               
               
                   
               
               
                 69 
                 pNOP484623 
                 ARID1A 
                 SHQLQHPHHTVRSPHCQA 
                 &lt;0.1 
               
               
                   
               
               
                 70 
                 pNOP503306 
                 ARID1A 
                 PSTEPPEHQDPRGRTPQ 
                 &lt;0.1 
               
               
                   
               
               
                 71 
                 pNOP526697 
                 ARID1A 
                 PRTENATGSWEVQQGV 
                 &lt;0.1 
               
               
                   
               
               
                 72 
                 pNOP532250 
                 ARID1A 
                 SSSHGGWGRRRRTSRS 
                 &lt;0.1 
               
               
                   
               
               
                 73 
                 pNOP535077 
                 ARID1A 
                 WELDLLMDKGLIVWLA 
                 &lt;0.1 
               
               
                   
               
               
                 74 
                 pNOP536697 
                 ARID1A 
                 AFSQDPPACLIYLVQ 
                 &lt;0.1 
               
               
                   
               
               
                 75 
                 pNOP539995 
                 ARID1A 
                 EFRGHQGEQQVSIWH 
                 &lt;0.1 
               
               
                   
               
               
                 76 
                 pNOP561120 
                 ARID1A 
                 WGACPMSQIRILMAA 
                 &lt;0.1 
               
               
                   
               
               
                 77 
                 pNOP564630 
                 ARID1A 
                 CPSSLVSWQRAHGH 
                 &lt;0.1 
               
               
                   
               
               
                 78 
                 pNOP568326 
                 ARID1A 
                 GDSLFRQGQASFRE 
                 &lt;0.1 
               
               
                   
               
               
                 79 
                 pNOP580855 
                 ARID1A 
                 QWPAALADWWGGHH 
                 &lt;0.1 
               
               
                   
               
               
                 80 
                 pNOP583798 
                 ARID1A 
                 SCCTTSTQNGSRHH 
                 &lt;0.1 
               
               
                   
               
               
                 81 
                 pNOP584557 
                 ARID1A 
                 SLHVLRAGPQRRDG 
                 &lt;0.1 
               
               
                   
               
               
                 82 
                 pNOP596649 
                 ARID1A 
                 GEGHGHDKSACCG 
                 &lt;0.1 
               
               
                   
               
               
                 83 
                 pNOP600191 
                 ARID1A 
                 IPSTSCCMMTTAS 
                 &lt;0.1 
               
               
                   
               
               
                 84 
                 pNOP600818 
                 ARID1A 
                 KCRRQVPQYLPRT 
                 &lt;0.1 
               
               
                   
               
               
                 85 
                 pNOP616167 
                 ARID1A 
                 TGRRPSPRHLCSC 
                 &lt;0.1 
               
               
                   
               
               
                 86 
                 pNOP616285 
                 ARID1A 
                 THWFHKSFVMYCF 
                 &lt;0.1 
               
               
                   
               
               
                 87 
                 pNOP624639 
                 ARID1A 
                 EEDVGGPLSGLH 
                 &lt;0.1 
               
               
                   
               
               
                 88 
                 pNOP628397 
                 ARID1A 
                 GSLWQHEESSRE 
                 &lt;0.1 
               
               
                   
               
               
                 89 
                 pNOP643975 
                 ARID1A 
                 RTRTGTRALGPP 
                 &lt;0.1 
               
               
                   
               
               
                 90 
                 pNOP650952 
                 ARID1A 
                 WTSRKTDHSHYG 
                 &lt;0.1 
               
               
                   
               
               
                 91 
                 pNOP658966 
                 ARID1A 
                 GCSARHHVAGA 
                 &lt;0.1 
               
               
                   
               
               
                 92 
                 pNOP667279 
                 ARID1A 
                 LMKRRRNRTKG 
                 &lt;0.1 
               
               
                   
               
               
                 93 
                 pNOP700714 
                 ARID1A 
                 KTLEPRRHGG 
                 &lt;0.1 
               
               
                   
               
               
                 94 
                 pNOP704301 
                 ARID1A 
                 MTSPWGQKEL 
                 &lt;0.1 
               
               
                   
               
               
                 95 
                 pNOP708028 
                 ARID1A 
                 PSTSVSSQGC 
                 &lt;0.1 
               
               
                   
               
               
                 96 
                 pNOP708425 
                 ARID1A 
                 QASSKDRTEE 
                 &lt;0.1 
               
               
                   
               
               
                 97 
                 pNOP709605 
                 ARID1A 
                 QSEDGAWNRA 
                 &lt;0.1 
               
               
                   
               
               
                 98 
                 pNOP718154 
                 ARID1A 
                 TRRGRRRGSS 
                 &lt;0.1 
               
               
                   
               
               
                 99 
                 pNOP76377 
                 ARID1A 
                 FQEVPAQDPASLSCGIRIYAGAPDSPVNQQFHGRRRRLKATNSSIHTTQSDPPIARHEQEQFSWDPGC 
                 &lt;0.1 
               
               
                   
                   
                   
                 L 
                   
               
               
                   
               
               
                 100 
                 pNOP84384 
                 ARID1A 
                 PKEPGVPGDGCGTAGQPGSGGQPGSSCHCSAEGQYRQPPGLPRGQPCRHTVPAEPGQPPPHAEPTL 
                 &lt;0.1 
               
               
                   
               
               
                 101 
                 pNOP86506 
                 ARID1A 
                 KGGGTGPRGELQQSGVVVGLLGDAPGKHLGYTRQHLGAVGPISIPREHLPACPGRTPTLGSLPFS 
                 &lt;0.1 
               
               
                   
                   
                   
                 RGLNPMPSTCSLVPSALTPWVLCLISRTARDGSSPLATSAPVCTGAQWMLGGAAGIGAEFWSIGHGG 
                   
               
               
                   
                   
                   
                 RGKSQLTWRLQRRTRPLCTAPPLPQSPQVVRTPHWTQMFLSLELLSATRPFRTWTLHCGQIQAAPLLQ 
                   
               
               
                   
               
               
                 102 
                 pNOP6876 
                 KMT2B 
                 PPVLFRGLESKCPTTRHPGGPWGVSPLAPCPPLEVHLH 
                 1.70 
               
               
                   
                   
                   
                 RRCCPGIPMNLLRPPLVLQAHAGGRELGGPGRRWWPTQGPRSRTPSCSASQLGAASNSDPPMISSRI 
                   
               
               
                   
               
               
                 103 
                 pNOP9663 
                 KMT2B 
                 RMTRSPGAPLLLGVGPPEKMSCHCQNLRSRAGPANLPCSLCCSSRPEGAWTRMLWPLAPLLLFPMAG 
                 0.94 
               
               
                   
                   
                   
                 LESRSLPMVCTASVWILRRIVI 
                   
               
               
                   
                   
                   
                 VPAPPVSSRHPGDLWMKTPPNPQRWRSHLSCDLPLPPPHLFPRSQHQSPLHHVPQLLHLPQFHSLRR 
                   
               
               
                   
               
               
                 104 
                 pNOP73574 
                 KMT2B 
                 DGPS 
                 0.75 
               
               
                   
               
               
                 105 
                 pNOP212366 
                 KMT2B 
                 PTTSPQWETRTSQLPPDVPVVPALWLPGRLHHGGPPLL 
                 0.57 
               
               
                   
               
               
                 106 
                 pNOP284432 
                 KMT2B 
                 GVLGMEVLALERSHSPRRLPWLMAASPPKA 
                 0.57 
               
               
                   
               
               
                 107 
                 pNOP339832 
                 KMT2B 
                 QMWLLPPQRPLPGNGVRKAQNGWCRH 
                 0.57 
               
               
                   
                   
                   
                 VCSPLCQGAPRWCACCVPAKDSTSWCSVKSAVTHSTHSAWRRPSGPCPSITTPGAAVAANSATSVDA 
                   
               
               
                   
                   
                   
                 KVVDPSTSWSASAAAMHTTRPVWGPAIQPGPRANGATGSVQPVCAVRAVGQLQARTGTSSGLEITA 
                   
               
               
                   
               
               
                 108 
                 pNOP8413 
                 KMT2B 
                 SAPGAPSYMRKETTARSVHAAMKTTTMRAR 
                 0.57 
               
               
                   
               
               
                 109 
                 pNOP149964 
                 KMT2B 
                 RPPQTPKGGGLTCPATSHYHLPTCSPGASTSPLSTTCPNSSIYPSSTP 
                 0.38 
               
               
                   
               
               
                 110 
                 pNOP346473 
                 KMT2B 
                 DDPPSSSSPSRCGSYPPKDPCPETG 
                 0.38 
               
               
                   
               
               
                 111 
                 pNOP102672 
                 KMT2B 
                 AVGQPARPARPSASRGCPLSPAGPRQHLPHTKPPGWMKMERPQRIPLRFQGLAVAGLAV 
                 0.19 
               
               
                   
               
               
                 112 
                 pNOP142719 
                 KMT2B 
                 GLPWSSRPTPGGGSWGAPGGGGGPPRARGAGLPPAAQVSSALRQTATLL 
                 0.19 
               
               
                   
                   
                   
                 GRGVPSRGSSSEQRATDTGSATAAPAGLANPAPAPGTTATTATAAATAVTTADASPGKSPDCGRGFLA 
                   
               
               
                   
               
               
                 113 
                 pNOP17169 
                 KMT2B 
                 AVWGRGEDVQPPQESQSAAIQDRSAAAAEGGSFHAAEPWRADGGGGRGCQADLRQRPCPV 
                 0.19 
               
               
                   
               
               
                 114 
                 pNOP172961 
                 KMT2B 
                 VGRDSWASTMMLSSSWPSSSPEPSVASTISSVTTSRERARRSRP 
                 0.19 
               
               
                   
                   
                   
                 LCGAAVARRGRAEPSPGRTRPCSVCWGSAGACAGSAACGPARGSSGAGDGVGAGAGARVEAACRR 
                   
               
               
                   
               
               
                 115 
                 pNOP20643 
                 KMT2B 
                 RRAVTGNPTRRSFRVFIQMKMWPPVPCALRSDPSEVERPEVGVASIRRPPFLLLA 
                 0.19 
               
               
                   
               
               
                 116 
                 pNOP233428 
                 KMT2B 
                 ERAALRSRVPCARSPHQTCLPSCCCGPGSGPGHGA 
                 0.19 
               
               
                   
                   
                   
                 WTPRCMAMPPASSTTPVSPTASLGSSTWRARNTLLSSPCAASCVVRSSPTTTSSPSRMPATSCPATVA 
                   
               
               
                   
               
               
                 117 
                 pNOP35490 
                 KMT2B 
                 PSAAVGSLTEAVAAHHDPSHLLLPSLPSCP 
                 0.19 
               
               
                   
               
               
                 118 
                 pNOP443670 
                 KMT2B 
                 SRKCKRPEGMPDSDISPLVE 
                 0.19 
               
               
                   
               
               
                 119 
                 pNOP482268 
                 KMT2B 
                 REPGPKTDWPTSALRDQQ 
                 0.19 
               
               
                   
                   
                   
                 APTSCGSSETSDWQLEMQGGARSRTWDPQAWRTVKPWRPWRQGPRPRWWAPLCDQVCFKGQK 
                   
               
               
                   
               
               
                 120 
                 pNOP54281 
                 KMT2B 
                 SKDGTIVLGTRIRSRSRST 
                 0.19 
               
               
                   
               
               
                 121 
                 pNOP81603 
                 KMT2B 
                 LLQPLHLLHPSHPLRHLLHPHSALHHHPQCPHHLYHPLHRLLPKRSRRNPLLLWSQLRAPGRGAGLP 
                 0.19 
               
               
                   
                   
                   
                 RLRDPFRTARLGAVHLRTVCWGSAAPLARGPERGPPGGPAPGAPGPAELQGGGPTAALHPVWARW 
                   
               
               
                   
                   
                   
                 EATAPRTLRPASCESALRGWPLQVCAQLHGGHGGHPHAALGGGRDPGPPGWRPDEGAPAEAARICV 
                   
               
               
                   
               
               
                 122 
                 pNOP1023 
                 KMT2B 
                 RLVRRPRPQVLATEYPAAKRSPSQCGVAPIPGSCLCAVETAGTRDPRIRAASRGSLSSIPGQGSGCLLT 
                 &lt;0.1 
               
               
                   
                   
                   
                 PGGPPSVCTLPQIRGCRLQGGGAALVHRAERVDTRQLCHLVGGSLRGERRLPQECACCCGPREADALRA 
                   
               
               
                   
                   
                   
                 LPEAWRHGGLLPVLLPQQLPLHVCPGQLLHLPG 
                   
               
               
                   
               
               
                 123 
                 pNOP109317 
                 KMT2B 
                 ALPGRDCSRWGHGEQPRGPGGQLRGGVQPHLPLHPLPCDCGVRPWSGPQRYPWSPPH 
                 &lt;0.1 
               
               
                   
               
               
                 124 
                 pNOP113418 
                 KMT2B 
                 GAEPAPQTYPAACVAAQGPKAPGQGCFGPWPLCFFSQWLDWKAEVSRWCAPRPCGF 
                 &lt;0.1 
               
               
                   
                   
                   
                 AVGQPARPARPSASRGCPLSPAGPRQHLPHTKPPGWMKMERPQRIPLRFQGLAVAGPSRNGPLCCH 
                   
               
               
                   
                   
                   
                 FRKMVLPRSPMVPQTCCLSPSGTTIQVRLRALRKSLHPQMIKRTRPQNGLAHICASRSAVRMGSALRQ 
                   
               
               
                   
               
               
                 125 
                 pNOP12376 
                 KMT2B 
                 RAWRGRGEL 
                 &lt;0.1 
               
               
                   
                   
                   
                 NLRSAGSTPTTPSTGDGVPGCQTESFPMRCCPHPWIMSMRSGDSRNQRPQNQGSLQGIPQQHSRA 
                   
               
               
                   
                   
                   
                 RIRLPSHTWRTPVSVHSASNTGMQTPRRRGGSCTSGRTSGHTSTVPSGRRKSSRRTTAPSRMCMLLW 
                   
               
               
                   
               
               
                 126 
                 pNOP12501 
                 KMT2B 
                 PEGGRCAASSA 
                 &lt;0.1 
               
               
                   
               
               
                 127 
                 pNOP129859 
                 KMT2B 
                 KPPLSSGCPLLPQSSQPSHLPQGSWLPLARPHLHHPLKTWAQTSRTWRWCQD 
                 &lt;0.1 
               
               
                   
               
               
                 128 
                 pNOP137356 
                 KMT2B 
                 CSAHSAITGCMPSARGSQMKTTRSFQDCQTRCCTPADRVLGQRSPAGERP 
                 &lt;0.1 
               
               
                   
               
               
                 129 
                 pNOP139147 
                 KMT2B 
                 LWCPPLVWPPALPLEPPALNSWTAWTTALTVRLRRCSSLGARARLLRGQE 
                 &lt;0.1 
               
               
                   
                   
                   
                 APLAHSEPGPSTAARFRQRPSSSPPFFFGGSNQSAQLLAIPEALGGCLLWPPALPWKSIFTDPPHPHSG 
                   
               
               
                   
               
               
                 130 
                 pNOP14051 
                 KMT2B 
                 RPGLPSSPQTFPSSQPFGSQAASITVGLPSSKNLPSAQGAPSYLSRHSPHTYLRGAGSPWPGPISTTP 
                 &lt;0.1 
               
               
                   
               
               
                 131 
                 pNOP145287 
                 KMT2B 
                 SLAPRWAAACPPASATSTSCVPGPATASSRMTRKSSARNTLISWMARKL 
                 &lt;0.1 
               
               
                   
               
               
                 132 
                 pNOP159086 
                 KMT2B 
                 LPASGRSGKLLGQGQRAPLLPLQPPAPPREALRKTVPPWPPKAPPS 
                 &lt;0.1 
               
               
                   
               
               
                 133 
                 pNOP160746 
                 KMT2B 
                 RWRGLRGYPSGSRAWQWRAPPGTVPFAATSGRWSSPGPRWSPRPAA 
                 &lt;0.1 
               
               
                   
               
               
                 134 
                 pNOP170320 
                 KMT2B 
                 LNFSGGPRHPKHPGAGHVSPPPPGGLGDGPQDGQQAPAGGSSKQ 
                 &lt;0.1 
               
               
                   
               
               
                 135 
                 pNOP170722 
                 KMT2B 
                 NIRLAAGNARRGPVQDLGPPGVEDSQAVEAVEAGAAAEVVGSPL 
                 &lt;0.1 
               
               
                   
               
               
                 136 
                 pNOP170957 
                 KMT2B 
                 PGSCPLLPQPLHLPRPPPHPLLLPPPPGGPYSFGPLSLPQAKPT 
                 &lt;0.1 
               
               
                   
               
               
                 137 
                 pNOP172435 
                 KMT2B 
                 SSHLCPPPFPPRLPPPGLCPQAPSSACCPWSEWSALPRPRHPLP 
                 &lt;0.1 
               
               
                   
               
               
                 138 
                 pNOP173362 
                 KMT2B 
                 WRRRRAAAVAPGLAPRGAASRAGRGAPAGAGAAADGATGPKECG 
                 &lt;0.1 
               
               
                   
               
               
                 139 
                 pNOP181020 
                 KMT2B 
                 FRERVADGGPECAHLCARGPPDGVLAVCQQRTPRAGVLSSLL 
                 &lt;0.1 
               
               
                   
               
               
                 140 
                 pNOP183367 
                 KMT2B 
                 PGSAWGARWGRKSWAPPGTVPFAATSGRWSSPGPRWSPRPAA 
                 &lt;0.1 
               
               
                   
               
               
                 141 
                 pNOP199665 
                 KMT2B 
                 VSASRMATTSLCTASWRTWWASSCGTRRRERPRTAGLEAR 
                 &lt;0.1 
               
               
                   
               
               
                 142 
                 pNOP207889 
                 KMT2B 
                 ALHPPAVSGTAPRTASRPLQEEAASSSGGRSSCDNPQT 
                 &lt;0.1 
               
               
                   
               
               
                 143 
                 pNOP2249 
                 KMT2B 
                 VPLPPAGRGPGGAAPESPWGCSGRGLSPLCLQQYIPPSPAATCRKCTFDMFNFLASQHRVLPEGATCD 
                 &lt;0.1 
               
               
                   
                   
                   
                 EEEDEVQLRSTRRATSLELPMAMRFRHLKKTSKEAVGVYRSAIHGRGLFCKRNIDAGEMVIEYSGIVIR 
                   
               
               
                   
                   
                   
                 SVLTDKREKFYDGKGIGCYMFRMDDFDVVDATMHGNAARFINHSCEPNCFSRVIHVEGQKHIVIFALRR 
                   
               
               
                   
                   
                   
                 ILRGEELTYDYKFPIEDASNKLPCNCGAKRCRRFLN 
                   
               
               
                   
                   
                   
                 DGGGGGRRQLPRAWLRAGPLPGPAAGRRRGRGPRRTGQRGRKSAGSSAARRWRDGAGRSRARGG 
                   
               
               
                   
               
               
                 144 
                 pNOP23566 
                 KMT2B 
                 HGPAPFAGAPPGPAPAPPPVGRPAGPAGPGTGSGPGLGPESRLRAGGGEQ 
                 &lt;0.1 
               
               
                   
               
               
                   
                   
                   
                 NGGGGGRRQLPRAWLRAGPLPGPAAGRRRGRGPRRTGQRGRKSAGSSAARRWRDGAGRSRARGG 
                   
               
               
                   
               
               
                 145 
                 pNOP23765 
                 KMT2B 
                 HGPAPFAGAPPGPAPAPPPVGRPAGPAGPGTGSGPGLGPESRLRAGGGEQ 
                 &lt;0.1 
               
               
                   
               
               
                 146 
                 pNOP252560 
                 KMT2B 
                 GGAAASGPGHASFGARSSPGRGPWGCRGQGPAS 
                 &lt;0.1 
               
               
                   
                   
                   
                 KPPQCVGSLTWIGLGSPLGKKVLGPSRNGPLCCHFRKMVLPRSPMVPQTCCLSPSGTTIQVRLRALRKS 
                   
               
               
                   
               
               
                 147 
                 pNOP25410 
                 KMT2B 
                 LHPQMIKRTRPQNGLAHICASRSAVRMGSALRQRAWRGRGEL 
                 &lt;0.1 
               
               
                   
               
               
                 148 
                 pNOP263780 
                 KMT2B 
                 IPMGLLGQRSISALSSTVYSSFPCCHLQEVHL 
                 &lt;0.1 
               
               
                   
               
               
                 149 
                 pNOP269620 
                 KMT2B 
                 VPLPPAGRGPGGAAPESPWGCSGRGLSPEVHL 
                 &lt;0.1 
               
               
                   
                   
                   
                 IPMGLLGQRSISGSAPLTCSTSWPPSTGCSLRGPPVMRKRMRCSSGQPDVPPAWSCPWPCVFVTLRR 
                   
               
               
                   
               
               
                 150 
                 pNOP27215 
                 KMT2B 
                 RPKKLWVSTDQPSTGEACSVSATSTRGRWSSSTLALSSARC 
                 &lt;0.1 
               
               
                   
               
               
                 151 
                 pNOP278498 
                 KMT2B 
                 RRRCSASSREPKCSYSRSISSSSRRWQLPCR 
                 &lt;0.1 
               
               
                   
               
               
                 152 
                 pNOP281826 
                 KMT2B 
                 APRWWAHCCSAPSVGQMGSNCTQDPAACKL 
                 &lt;0.1 
               
               
                   
               
               
                 153 
                 pNOP283728 
                 KMT2B 
                 GAHLRLQVPHRGCQQQAALQLWRQALPSVP 
                 &lt;0.1 
               
               
                   
               
               
                 154 
                 pNOP287880 
                 KMT2B 
                 PLGPWGAATGARGTAPRRSPAPPPATSTSL 
                 &lt;0.1 
               
               
                   
               
               
                 155 
                 pNOP295363 
                 KMT2B 
                 GKLAGCPPKKSWIWTGREPLLEKAGTEAG 
                 &lt;0.1 
               
               
                   
               
               
                 156 
                 pNOP295589 
                 KMT2B 
                 GRELGGGVENSDRESARGPRACPTQTSLL 
                 &lt;0.1 
               
               
                   
               
               
                 157 
                 pNOP306682 
                 KMT2B 
                 ELWGNSRQELGRRVVWRLQPLPQVHPAI 
                 &lt;0.1 
               
               
                   
               
               
                 158 
                 pNOP317592 
                 KMT2B 
                 AQLLLSGHPRGGPETHCYLRPAPHPAW 
                 &lt;0.1 
               
               
                   
               
               
                 159 
                 pNOP323657 
                 KMT2B 
                 LRPWLPTTTPHTSCCRRCHLAPSLGAP 
                 &lt;0.1 
               
               
                   
               
               
                 160 
                 pNOP326541 
                 KMT2B 
                 RCPSPQCPPSPGSAGPRHRGYIIGVRD 
                 &lt;0.1 
               
               
                   
               
               
                 161 
                 pNOP328068 
                 KMT2B 
                 SGQGSLGLQGTGPGLLRTCHRKLWILC 
                 &lt;0.1 
               
               
                   
               
               
                 162 
                 pNOP331404 
                 KMT2B 
                 ALALPLSPPNPPHPKSYLSTSWGKYL 
                 &lt;0.1 
               
               
                   
               
               
                 163 
                 pNOP331561 
                 KMT2B 
                 APQTRHIQNHTCQQAGASICEDGWGG 
                 &lt;0.1 
               
               
                   
               
               
                 164 
                 pNOP340189 
                 KMT2B 
                 RCGPQFPALCAPIPARSSAPRSGSQA 
                 &lt;0.1 
               
               
                   
               
               
                 165 
                 pNOP363468 
                 KMT2B 
                 GPAIGNCGFCVEEPRGSWGWRCWP 
                 &lt;0.1 
               
               
                   
               
               
                 166 
                 pNOP367137 
                 KMT2B 
                 LTSGRSSTMGRASGAICSAWMTLM 
                 &lt;0.1 
               
               
                   
               
               
                 167 
                 pNOP370489 
                 KMT2B 
                 RGRREERRRRKRQGGRREGRKSCS 
                 &lt;0.1 
               
               
                   
               
               
                 168 
                 pNOP373366 
                 KMT2B 
                 TPMVLMFSAESMWTSRASTSSGSS 
                 &lt;0.1 
               
               
                   
               
               
                 169 
                 pNOP376070 
                 KMT2B 
                 ASGSGPHQPPQPASIRPCGHHSC 
                 &lt;0.1 
               
               
                   
               
               
                 170 
                 pNOP378678 
                 KMT2B 
                 GAAQVNQTCHQPGAAHGHAFSSP 
                 &lt;0.1 
               
               
                   
               
               
                 171 
                 pNOP384879 
                 KMT2B 
                 PHPHICLAPRGPRGPGVKPWPCP 
                 &lt;0.1 
               
               
                   
               
               
                 172 
                 pNOP392368 
                 KMT2B 
                 AQHRRGGDGHRVLWHCHPLGVD 
                 &lt;0.1 
               
               
                   
               
               
                 173 
                 pNOP393358 
                 KMT2B 
                 CSPPSLCGLRGHQLQAEVLDGA 
                 &lt;0.1 
               
               
                   
               
               
                 174 
                 pNOP394645 
                 KMT2B 
                 EQDDAVRTVRSLGACQVRGALR 
                 &lt;0.1 
               
               
                   
               
               
                 175 
                 pNOP402065 
                 KMT2B 
                 PPAQLTPPAHLPGSQGPQGSGC 
                 &lt;0.1 
               
               
                   
               
               
                 176 
                 pNOP407306 
                 KMT2B 
                 TSPSLGALTPRSSAVYTGSVTK 
                 &lt;0.1 
               
               
                   
               
               
                 177 
                 pNOP411745 
                 KMT2B 
                 EDVQRSCGCLQISHPRARPVL 
                 &lt;0.1 
               
               
                   
                   
                   
                 TCPTPSEAATFAPHHFPHGSHLLDSAPRPPPRRAARGRSGPPCPAPATPSPDAGAEQWASQPAPPGH 
                   
               
               
                   
               
               
                 178 
                 pNOP41189 
                 KMT2B 
                 PRQEGVHFLRPVPASTSPIQSPPAG 
                 &lt;0.1 
               
               
                   
               
               
                 179 
                 pNOP426146 
                 KMT2B 
                 VLLTWTSRPACWGLSPSRKRL 
                 &lt;0.1 
               
               
                   
               
               
                 180 
                 pNOP459923 
                 KMT2B 
                 QAGEVLRWEGHRVLYVPHG 
                 &lt;0.1 
               
               
                   
               
               
                 181 
                 pNOP462749 
                 KMT2B 
                 RWRGLRGYPSGSRAWQWRV 
                 &lt;0.1 
               
               
                   
               
               
                 182 
                 pNOP468831 
                 KMT2B 
                 CCHLPGRAAPRSPALPAL 
                 &lt;0.1 
               
               
                   
               
               
                 183 
                 pNOP469462 
                 KMT2B 
                 CSGRHDAWQCRPLHQPLL 
                 &lt;0.1 
               
               
                   
               
               
                 184 
                 pNOP483192 
                 KMT2B 
                 RPGPRLRGHGGGVRTECC 
                 &lt;0.1 
               
               
                   
               
               
                 185 
                 pNOP499276 
                 KMT2B 
                 LGARGPPCSSASDPPRK 
                 &lt;0.1 
               
               
                   
               
               
                 186 
                 pNOP533725 
                 KMT2B 
                 TSPAGPGTPSTPEPGM 
                 &lt;0.1 
               
               
                   
               
               
                 187 
                 pNOP536795 
                 KMT2B 
                 AGPSRGACARCSRAC 
                 &lt;0.1 
               
               
                   
               
               
                 188 
                 pNOP538448 
                 KMT2B 
                 CQLRKRKRQSCHHRL 
                 &lt;0.1 
               
               
                   
               
               
                 189 
                 pNOP546704 
                 KMT2B 
                 KRPDDSEDAVALGFR 
                 &lt;0.1 
               
               
                   
                   
                   
                 PIPPILPGGGRAAPAPASRHLVLPSLQILPRLWTQRSWIQAPPGVRALPPCIPPGLSGAQLSNPGHAQT 
                   
               
               
                   
               
               
                 190 
                 pNOP56683 
                 KMT2B 
                 APLDLFSLCAL 
                 &lt;0.1 
               
               
                   
               
               
                 191 
                 pNOP569191 
                 KMT2B 
                 GPPTGHRCSCPWSS 
                 &lt;0.1 
               
               
                   
               
               
                 192 
                 pNOP581470 
                 KMT2B 
                 RGIRRGGVSGFSFR 
                 &lt;0.1 
               
               
                   
               
               
                 193 
                 pNOP582085 
                 KMT2B 
                 RLGRWNDWLKKAGR 
                 &lt;0.1 
               
               
                   
               
               
                 194 
                 pNOP599417 
                 KMT2B 
                 HVQLPGLPAPGAP 
                 &lt;0.1 
               
               
                   
               
               
                 195 
                 pNOP607050 
                 KMT2B 
                 PCEDENPHSAWGP 
                 &lt;0.1 
               
               
                   
                   
                   
                 ECPVTVPAGKGGGSRPWGRIRAHRFWRDPGPHTPALTALPSRQEDAHGSMWTLSGLPTCAGLWVL 
                   
               
               
                   
               
               
                 196 
                 pNOP60902 
                 KMT2B 
                 CQLPRQAQVWGP 
                 &lt;0.1 
               
               
                   
               
               
                 197 
                 pNOP609760 
                 KMT2B 
                 QSPNLSPHLLWFQ 
                 &lt;0.1 
               
               
                   
               
               
                 198 
                 pNOP614494 
                 KMT2B 
                 SPGWQGNCEPRWF 
                 &lt;0.1 
               
               
                   
               
               
                 199 
                 pNOP616888 
                 KMT2B 
                 TRCHQRAHWFHPH 
                 &lt;0.1 
               
               
                   
               
               
                 200 
                 pNOP619315 
                 KMT2B 
                 WQPALPRPDRQPS 
                 &lt;0.1 
               
               
                   
               
               
                 201 
                 pNOP625450 
                 KMT2B 
                 ERKLLPDLYTLL 
                 &lt;0.1 
               
               
                   
                   
                   
                 EETVHPKGTHISLDLTDPGAAPSSPSPSTSPGPLPTPCSCHLLPEAPTPSGPSVYPKRSPPEDLRIGAY 
                   
               
               
                   
                   
                   
                 SSS 
                   
               
               
                   
               
               
                 202 
                 pNOP62604 
                 KMT2B 
                 SWGS 
                 &lt;0.1 
               
               
                   
               
               
                 203 
                 pNOP644158 
                 KMT2B 
                 RWLGRVNLSHPQ 
                 &lt;0.1 
               
               
                   
               
               
                 204 
                 pNOP650472 
                 KMT2B 
                 WNEWGETPGHPP 
                 &lt;0.1 
               
               
                   
               
               
                 205 
                 pNOP660324 
                 KMT2B 
                 GRHRTDGAGTD 
                 &lt;0.1 
               
               
                   
               
               
                 206 
                 pNOP661817 
                 KMT2B 
                 HQEAVLCIPEV 
                 &lt;0.1 
               
               
                   
               
               
                 207 
                 pNOP673600 
                 KMT2B 
                 QNRGSEDGTTG 
                 &lt;0.1 
               
               
                   
               
               
                 208 
                 pNOP675110 
                 KMT2B 
                 RGVTPPGASPG 
                 &lt;0.1 
               
               
                   
               
               
                 209 
                 pNOP706730 
                 KMT2B 
                 PGLRGQPAGD 
                 &lt;0.1 
               
               
                   
               
               
                 210 
                 pNOP711022 
                 KMT2B 
                 RISGSLLCLW 
                 &lt;0.1 
               
               
                   
                   
                   
                 SLGLRGTALPHWLPVLPSVLEHSGCSEALLVSVPNSGVSAMGAEGRASSPGGCRGEPDHCAQPRPFLR 
                   
               
               
                   
               
               
                 211 
                 pNOP71226 
                 KMT2B 
                 APRW 
                 &lt;0.1 
               
               
                   
               
               
                 212 
                 pNOP720871 
                 KMT2B 
                 WNDWLKKAGR 
                 &lt;0.1 
               
               
                   
                   
                   
                 RWDNCPWDSNQVKVKVNMRKVGRMSPKEELDLDREGALAGKSRNRSWMTRKKRRKKKKKKTRRE 
                   
               
               
                   
               
               
                 213 
                 pNOP73224 
                 KMT2B 
                 KRRKKEL 
                 &lt;0.1 
               
               
                   
                   
                   
                 ALEGRWRRWPGLSSRSPTEALSGLKMSRWKLRESGPQVPSPLCKVPASNMSAVMLLWPWVRPGPW 
                   
               
               
                   
                   
                   
                 CLKMSLASVPSLSGIGRTSPQRIHHRRPRLRVSRHGPGGERWRQQALGENQSPQVLEGPWPTHPGAH 
                   
               
               
                   
               
               
                 214 
                 pNOP8126 
                 KMT2B 
                 CPPITARRCAWLDVDTVGAAYVCRTVGPVSTA 
                 &lt;0.1 
               
               
                   
               
               
                 215 
                 pNOP82310 
                 KMT2B 
                 RSTNRCLLLLLLGLLKPLSQSLLLPMTLQLSLSLGQWAAPTTSACLDSPLWSPLLLRPRCPLTGLQL 
                 &lt;0.1 
               
               
                   
                   
                   
                 GDDASCGKGRGKAATTASDSSSPFTSSTPPTPFDISSTPTLPSTTTPSVPTTSTIPSTASCPRGAGGIP 
                   
               
               
                   
                   
                   
                 SSCGPSYVLQEEGPASPDSQPAGGAGSCSGRARGHLSSHSNPQHRHGRPSGRQSHRGPQKHHLPEEYPA 
                   
               
               
                   
               
               
                 216 
                 pNOP8822 
                 KMT2B 
                 VYYACGECPLLPCHQDTPAIYG 
                 &lt;0.1 
               
               
                   
               
               
                 217 
                 pNOP99414 
                 KMT2B 
                 ATGHRHRLSYCSPCRPCKPSSCPRHYRHHSHSCSHRRHHSRCLPWKKPGLRAWVPCRCLG 
                 &lt;0.1 
               
               
                   
                   
                   
                 TRRCHCCPHLRSHPCPHHLRNHPRPHHLRHHACHHHLRNCPHPHFLRHCTCPGRWRNRPSLRRLRSL 
                   
               
               
                   
                   
                   
                 LCLPHLNHHLFLHWRSRPCLHRKSHPHLLHLRRLYPHHLKHRPCPHHLKNLLCPRHLRNCPLPRHLKHL 
                   
               
               
                   
                   
                   
                 ACLHHLRSHPCPLHLKSHPCLHHRRHLVCSHHLKSLLCPLHLRSLPFPHHLRHHACPHHLRTRLCPHHL 
                   
               
               
                   
                   
                   
                 KNHLCPPHLRYRAYPPCLWCHACLHRLRNLPCPHRLRSLPRPLHLRLHASPHHLRTPPHPHHLRTHLLP 
                   
               
               
                   
                   
                   
                 HHRRTRSCPCRWRSHPCCHYLRSRNSAPGPRGRTCHPGLRSRTCPPGLRSHTYLRRLRSHTCPPSLRSH 
                   
               
               
                   
                   
                   
                 AYALCLRSHTCPPRLRDHICPLSLRNCTCPPRLRSRTCLLCLRSHACPPNLRNHTCPPSLRSHACPPGL 
                   
               
               
                   
                   
                   
                 RNRICPLSLRSHPCPLGLKSPLRSQANALHLRSCPCSLPLGNHPYLPCLESQPCLSLGNHLCPLCPRSC 
                   
               
               
                   
                   
                   
                 RCPHLG 
                   
               
               
                   
               
               
                 218 
                 pNOP134 
                 KMT2D 
                 SHPCRLS 
                 2.08 
               
               
                   
                   
                   
                 ARVMPVPVFLAQSPSWALQTRRGVAPCPWSWGSLRMLVQPEMRAPYGSVLTHCQRLMTHYCAML 
                   
               
               
                   
               
               
                 219 
                 pNOP21934 
                 KMT2D 
                 GQLSAEAKLRGRRGGGAAPQPVPASNRVAAAVSQEDAGLVEEPMEDVVEDGPG 
                 1.89 
               
               
                   
               
               
                 220 
                 pNOP234091 
                 KMT2D 
                 GPRSHPLPRLWHLLLQVTQTSFALAPTLTHMLSPH 
                 1.51 
               
               
                   
                   
                   
                 PCHHCTSGANGEDGLASQARQDWRVLSPQMPLALMTRRMGTWTPMSCSRVKVVWSTWSAKLNW 
                   
               
               
                   
               
               
                 221 
                 pNOP22159 
                 KMT2D 
                 RAPSALMWSLAKRRPRKAKNASVNHIGLALVVSWCDSGNPTHARKRGLLHRRRC 
                 0.75 
               
               
                   
                   
                   
                 CCSRAGVVWSVLCVRCVARPPTPHACCSVMTVILATTHTAWTPHCSPSPRAAGSASGVCPVCSVGLLP 
                   
               
               
                   
               
               
                 222 
                 pNOP44838 
                 KMT2D 
                 LASTVNGRIVTHTVGPVPAW 
                 0.75 
               
               
                   
               
               
                 223 
                 pNOP111349 
                 KMT2D 
                 PTLRWGLGGSQQPCPRGQQVSSMPRSQVGSPPILSGPLGRVHLWAPPLPCVSLSLRQ 
                 0.38 
               
               
                   
               
               
                 224 
                 pNOP170800 
                 KMT2D 
                 NRLMRRLNGRPCCGGWSQDPWALRSALPLLLMPLNPAWHLCSLR 
                 0.38 
               
               
                   
               
               
                 225 
                 pNOP102126 
                 KMT2D 
                 TTVFIQHPTPRVLPCQLVWSWSTGPRRALSLAAPILWPWKLGSCPVRIPSWMTILMPTRP 
                 0.19 
               
               
                   
               
               
                 226 
                 pNOP129784 
                 KMT2D 
                 KHCSCYAQSTVRGLHIWRRLAVQCVRGQGSCVTCSSVPAVGITITGPAWTLL 
                 0.19 
               
               
                   
               
               
                 227 
                 pNOP139704 
                 KMT2D 
                 PSPGCSVPPSWHSRVRALWDTGWSQPSSSSSNNSTNSKGPWQGCPIFSRV 
                 0.19 
               
               
                   
               
               
                 228 
                 pNOP155302 
                 KMT2D 
                 RSPTPMRCCSQRAPPGQALSQRRGKLRVLVGRKRVWKARAQTLALIG 
                 0.19 
               
               
                   
                   
                   
                 KAAVRHCRGPFFKVDSLWAICPPAAQWTPTQASASPRSWILGSAGASLARNPVSPTAPGRAQVAPRP 
                   
               
               
                   
               
               
                 229 
                 pNOP16127 
                 KMT2D 
                 PPPQPPPRRVRATDSPITSGVFSAGRRMRSWASCPPSHLCSMPTLIFLISSKTTQTGQAVANKS 
                 0.19 
               
               
                   
                   
                   
                 WTARSWLVRIKIQNRQLMDLQLLRTQVPLSQTCPTHMWERSLSLVLGVPGFRRLLRTAVGVRCGVVL 
                   
               
               
                   
               
               
                 230 
                 pNOP17440 
                 KMT2D 
                 SVTAGSPVYTGSGSYGALSCHLIGPGVQWCPLGGAQGPMRQCCPVRTYHRLVSLRALHLPT 
                 0.19 
               
               
                   
                   
                   
                 KAAVRHCRGPFFKVDSLWAICPPAAQWTPTQASASPRSWILARNPVSPTAPGRAQVAPRPPPPQPPP 
                   
               
               
                   
               
               
                 231 
                 pNOP18835 
                 KMT2D 
                 RRVRATDSPITSGVFSAGRRMRSWASCPPSHLCSMPTLIFLISSKTTQTGQAVANKS 
                 0.19 
               
               
                   
               
               
                 232 
                 pNOP189145 
                 KMT2D 
                 LLGPNLRPLRAAVLCPLAHCPPTLSPECLPVLSPSPAPSLH 
                 0.19 
               
               
                   
                   
                   
                 TCWLPCLHPLTIRLRMSGWRVMRIAILLTALCQLHPLRASWGRRPLVSLIWAQAGGSKRTGPSPLSSPS 
                   
               
               
                   
               
               
                 233 
                 pNOP20393 
                 KMT2D 
                 FLGPASQSSQIPNLMGPLAWRSLESCLSQLGKRAKEVRCQSCSQSLLLQPRT 
                 0.19 
               
               
                   
                   
                   
                 NRRAPPQSHPLSTAIPTMSPIWMCDSSRPHLLKNPPRPLPPWHLLLPVPLLSPWLNFPPNPWLSHPSP 
                   
               
               
                   
               
               
                 234 
                 pNOP23772 
                 KMT2D 
                 HLCHWPHPLNQPDPSPVPGPLKKVKIPVLLASRNGKECAGSGFGCC 
                 0.19 
               
               
                   
               
               
                 235 
                 pNOP269687 
                 KMT2D 
                 VRTPTDWLLKGFGAWRYQVFPHRNPQPHRPLN 
                 0.19 
               
               
                   
               
               
                 236 
                 pNOP336175 
                 KMT2D 
                 KGTEGYFRGEESRPAGCLAYTPSQSD 
                 0.19 
               
               
                   
               
               
                 237 
                 pNOP352206 
                 KMT2D 
                 MASPHLKSWGSTPRMLPLPGIVKGH 
                 0.19 
               
               
                   
               
               
                 238 
                 pNOP376012 
                 KMT2D 
                 ARQPLDGLRWHHALHPHNPHHGG 
                 0.19 
               
               
                   
               
               
                 239 
                 pNOP490058 
                 KMT2D 
                 APVGGPPKRGDATAAPT 
                 0.19 
               
               
                   
                   
                   
                 GHQEPATTSCWQALAQKLGICSCRSYSGQRMCNSALGGGPRGCELRSTGTLTASWLGWSRNYRVPP 
                   
               
               
                   
               
               
                 240 
                 pNOP61039 
                 KMT2D 
                 ATRRMQQQGSL 
                 0.19 
               
               
                   
                   
                   
                 YRATTSQTRTCPPVWAGSAWGWNHAYGGSASSTAPRSPGQKPTAAALKSSAAAAATGTPHAAAAA 
                   
               
               
                   
                   
                   
                 AESGSTPDPTLPGAWDPDLSPPGPPGLPTSTWGLPWTTDRPPPGARGRASTSGPTPAPCPTRSLIYRTS 
                   
               
               
                   
               
               
                 241 
                 pNOP8118 
                 KMT2D 
                 PWPCPSHTSTIQPSRAKETFTITFPQLPASH 
                 0.19 
               
               
                   
               
               
                 242 
                 pNOP87579 
                 KMT2D 
                 SSGERFQQLTKPPTCKRPKITGQLTASTRCRSQGHWAARPPLLPPPFSLAAPLPPPACLPLRTGS 
                 0.19 
               
               
                   
               
               
                 243 
                 pNOP106859 
                 KMT2D 
                 HPGLCLLKLFAHHPLPLASSPLTLILAHPHALSPVTHLPHCISHPDPSPLKLPLRLGL 
                 &lt;0.1 
               
               
                   
                   
                   
                 FKAFTGKAAAAAAATYAAGPETAAAAAAATAAAAPSRTGGNPAATAAGSWSTDKPSSGSQAPGPYA 
                   
               
               
                   
                   
                   
                 SQQPPRPPGPAAVPSTTPGAPGHAGPCPGGCVAAAAPWSFGPPGPSQTGAYDPVPGAQFPPAGTA 
                   
               
               
                   
                   
                   
                 GSGPYGTQAGHSPAAAAATTAPTARVHGRAVPSSAESDVTQWAAQTERSAHGLFTAASAAAAAATA 
                   
               
               
                   
               
               
                 244 
                 pNOP1069 
                 KMT2D 
                 TATSAAAAAAATTATATSAATASTAATAAAASTTAAATASTAATAATTATATTTAAVSTAAATAADGP 
                 &lt;0.1 
               
               
                   
                   
                   
                 FKPESNFTVSSATTAAASGTWPWHASKASSTLF 
                   
               
               
                   
               
               
                 245 
                 pNOP108932 
                 KMT2D 
                 VPRWREFPPVCQALVSQCLVQLVLPSSLSCGTMYRKDWDLGALRFLVRAHLRDPVFTL 
                 &lt;0.1 
               
               
                   
               
               
                 246 
                 pNOP109806 
                 KMT2D 
                 EAPKLSISEHPILGPCPYSSNSNNCGSNNRQQQQPPCDLPCQLAFHQLLDLNLAAKP 
                 &lt;0.1 
               
               
                   
               
               
                 247 
                 pNOP110054 
                 KMT2D 
                 GEAQGGGGWTPPFSLPIHHCYPQGRARTCCQFPWPGAKARTEHDGQPGYPDGHRAIF 
                 &lt;0.1 
               
               
                   
                   
                   
                 APCQGPKWAAPQFCPVPWDGCICGHPLSHAFHFPSGSRGAFPKAPCPSAWSPATPWDQQPFWARP 
                   
               
               
                   
                   
                   
                 HLGQASKHKLHSSHRELPPIGQPPGAQQRVHRGELWAVPTTPSVGSATTCTRRIPPLPVPWSLTAIRH 
                   
               
               
                   
               
               
                 248 
                 pNOP11179 
                 KMT2D 
                 HLSCRKARRPRDWNG 
                 &lt;0.1 
               
               
                   
               
               
                 249 
                 pNOP114830 
                 KMT2D 
                 PSAPCASELVPPAAAIACVAPMSTILLVPSVPSACSSRTRPCCVQCIRSRGPVSKS 
                 &lt;0.1 
               
               
                   
               
               
                 250 
                 pNOP116135 
                 KMT2D 
                 WGSQMRLSCTRWRLRKFQNLNAQPWNPVPPVLSLPQWGTFPAPPPALPQPWMTSLA 
                 &lt;0.1 
               
               
                   
               
               
                 251 
                 pNOP118654 
                 KMT2D 
                 PGSSPHQQGAEARGTGQPAPRCCPHHFHWQPHYPRRLVYLCGRVPEAAGGLGAWP 
                 &lt;0.1 
               
               
                   
               
               
                 252 
                 pNOP118804 
                 KMT2D 
                 PSRRAVGGRRMSGKWQSLWSSLAQPCDLTRYRETCVAAVSVMRRVTGPLMGLPVC 
                 &lt;0.1 
               
               
                   
               
               
                 253 
                 pNOP118816 
                 KMT2D 
                 PTGPTSPHSPAARGTGQPAPRCCPHHFHWQPHYPRRLVYLCGRVPEAAGGLGAWP 
                 &lt;0.1 
               
               
                   
               
               
                 254 
                 pNOP127343 
                 KMT2D 
                 SGPCKIIQGHNLPNQDLSSSLGRVCLGLESCLRWVSFEHSSKESWPKTHSCGT 
                 &lt;0.1 
               
               
                   
               
               
                 255 
                 pNOP127724 
                 KMT2D 
                 TRTASGLWNPWPRRQPYATAEALSSRWTPFGQSALQQPNGLLPRPLPVPVPGF 
                 &lt;0.1 
               
               
                   
               
               
                 256 
                 pNOP137298 
                 KMT2D 
                 CLQSPPDPSGISGRAPEPGLGPKAPGATPCPGFGTFSSKSPRHLSPWLLH 
                 &lt;0.1 
               
               
                   
               
               
                 257 
                 pNOP137386 
                 KMT2D 
                 CSVAWLYPEEPTRHLEPPETGEPRPRATHSAQLYLQCLQSGCATALGPTS 
                 &lt;0.1 
               
               
                   
               
               
                 258 
                 pNOP142770 
                 KMT2D 
                 GPQKPREMEAQKGRNSPHRRKEMMVQILQMKNPVASRAKPIHQDLRMGA 
                 &lt;0.1 
               
               
                   
               
               
                 259 
                 pNOP143520 
                 KMT2D 
                 LCLLPALRGKACGACCTSRAGAHEGERARAPVLSLRRCVADRNWHGLAA 
                 &lt;0.1 
               
               
                   
               
               
                 260 
                 pNOP144316 
                 KMT2D 
                 PNRAGEATAAPATTRAADSAADPAQHPAAGEGNSCSSCRSSGASRQLGC 
                 &lt;0.1 
               
               
                   
               
               
                 261 
                 pNOP144483 
                 KMT2D 
                 PVRLTDRPYISAFPRSQGHWAARPPLLPPPFSLAAPLPPPACLPLRTGS 
                 &lt;0.1 
               
               
                   
               
               
                 262 
                 pNOP152835 
                 KMT2D 
                 GRSAQDPLPLWSLELSEMDELRSFEATRQGSPPTHNLFPERDEGEER 
                 &lt;0.1 
               
               
                   
               
               
                 263 
                 pNOP154481 
                 KMT2D 
                 PLWRSTPNASRQQGRAHHVKNRKSHVHRWPPHHPLSSNPTSLTRSLI 
                 &lt;0.1 
               
               
                   
               
               
                 264 
                 pNOP161094 
                 KMT2D 
                 SSGERFQQLTKPPTCKRPKITGQLTASTRCRSRLRARSTSRPRWAT 
                 &lt;0.1 
               
               
                   
               
               
                 265 
                 pNOP165656 
                 KMT2D 
                 QRIPYFLPKTTHGGTACSLLEVQGVPGVPGLWGGLSRTESQLGVV 
                 &lt;0.1 
               
               
                   
               
               
                 266 
                 pNOP169094 
                 KMT2D 
                 GKTQPLWMGLMLRVHSQSLDRPLAVWLVNLKAPLCSWTPRSWPL 
                 &lt;0.1 
               
               
                   
               
               
                 267 
                 pNOP172213 
                 KMT2D 
                 SHCKGQDGGFERHQESDGSGQHWGGTWYEQTASVSASPEALGGT 
                 &lt;0.1 
               
               
                   
               
               
                 268 
                 pNOP172370 
                 KMT2D 
                 SQLLLPLRLWLLTLIALPVRRRRKKMMTPCRIPWFSSPTQTNLS 
                 &lt;0.1 
               
               
                   
               
               
                 269 
                 pNOP172794 
                 KMT2D 
                 TRRGKALTLWGLTTPACPTPAPASAQLSAAAATSEASRTTAAAS 
                 &lt;0.1 
               
               
                   
                   
                   
                 RSRLVYTASPGRLCVPSSALPKKLAVSSQKLMLRSSSWLQSSRARSRNNWIRSGNSRRSTLISWQNIG 
                   
               
               
                   
                   
                   
                 TS 
                   
               
               
                   
               
               
                 270 
                 pNOP17361 
                 KMT2D 
                 SSNNSSSSSNNSNSTQLCWLSALPRVPGCSPSSLVSCSLAMGCSHHRGLRVGKPEVFA 
                 &lt;0.1 
               
               
                   
               
               
                 271 
                 pNOP174645 
                 KMT2D 
                 EEGAAEEAAAFSTVAACPAAAATAAAAFPTVCTRPCPGHVFAT 
                 &lt;0.1 
               
               
                   
               
               
                 272 
                 pNOP175361 
                 KMT2D 
                 GVAVPYPAAPTDAAEGARGADWCTPQVPEGSVCQAAHCQKSWP 
                 &lt;0.1 
               
               
                   
               
               
                 273 
                 pNOP178870 
                 KMT2D 
                 TISAWHWWFHGATAEIPHTHEKGACCTGGGVEWGWAARRGDTC 
                 &lt;0.1 
               
               
                   
               
               
                 274 
                 pNOP179906 
                 KMT2D 
                 ALPQAPTPGARPSAFAGPLWTGPCLSPGAPLPHGTAHLSPLS 
                 &lt;0.1 
               
               
                   
               
               
                 275 
                 pNOP182619 
                 KMT2D 
                 LPANVLAGSALNAKCAKPAGNLGMTLRCWFVRRVTKDTILSA 
                 &lt;0.1 
               
               
                   
               
               
                 276 
                 pNOP183568 
                 KMT2D 
                 PRGSRGDLAVICRTMWQLGVARSGVLVIPPSLVPTRPLLLRE 
                 &lt;0.1 
               
               
                   
               
               
                 277 
                 pNOP185368 
                 KMT2D 
                 TRVELYCLLSNNSSSKWHLALACQQSLFNTFLALEPWVQPSS 
                 &lt;0.1 
               
               
                   
               
               
                 278 
                 pNOP187538 
                 KMT2D 
                 FGSRSSATPCGRRRKQLQQLQEQWGLQAAGVLSPAALPLSS 
                 &lt;0.1 
               
               
                   
               
               
                 279 
                 pNOP188940 
                 KMT2D 
                 KTWRPMTPTWMTCSMETSLTCWHILILSWTLGTRRISSMST 
                 &lt;0.1 
               
               
                   
               
               
                 280 
                 pNOP191904 
                 KMT2D 
                 STPLVPKGTVTLSHRWLPPSWRHPSALHQKLTALTLSLSPL 
                 &lt;0.1 
               
               
                   
               
               
                 281 
                 pNOP193752 
                 KMT2D 
                 CRTCVWYVAALAGGQRATSLPVRSALSAITLTVSTARSPR 
                 &lt;0.1 
               
               
                   
               
               
                 282 
                 pNOP194798 
                 KMT2D 
                 GLICAPPAGSALCFLRGSAWVHDPEPSGPPTAHARAAHAK 
                 &lt;0.1 
               
               
                   
               
               
                 283 
                 pNOP198849 
                 KMT2D 
                 SRSNWQCSSSWQTASSQIQTWTNLLQKISLIPLQRPRWWL 
                 &lt;0.1 
               
               
                   
               
               
                 284 
                 pNOP198864 
                 KMT2D 
                 SSAATVNGGCMQAVRASSQRTMWSRQPMKALTVSPASPTW 
                 &lt;0.1 
               
               
                   
               
               
                 285 
                 pNOP199023 
                 KMT2D 
                 SYGGPCAAPDAGRLISSWGWPARGIPHYPTWHPQTPALHT 
                 &lt;0.1 
               
               
                   
               
               
                 286 
                 pNOP199159 
                 KMT2D 
                 TISAWHWWFHGATAEIPHTHEKGACCTGGGVEWGWAARRG 
                 &lt;0.1 
               
               
                   
                   
                   
                 GLFSQFGWVPTAAFPGSCRCPTARFAPATDAHPATSSCPPATPGSIHGYGVQSRAYAKWAAWRAGRL 
                   
               
               
                   
               
               
                 287 
                 pNOP20115 
                 KMT2D 
                 GTPAELTASAITEAHGHHATFHVHEAAAIGNAAAAGKQLLPRYRPGQICCRRYH 
                 &lt;0.1 
               
               
                   
               
               
                 288 
                 pNOP201536 
                 KMT2D 
                 ELLCSAPSLTALRPFLPSACQSSVPVQLPVSTDTPASVC 
                 &lt;0.1 
               
               
                   
               
               
                 289 
                 pNOP209010 
                 KMT2D 
                 EPWGRGRQSFRAPALAPTFWGVPEGPRGEEGRAWGILS 
                 &lt;0.1 
               
               
                   
               
               
                 290 
                 pNOP209424 
                 KMT2D 
                 GGEGAAAQLPSPFPHQTGSQQQFPRKTPASWRSPWRTW 
                 &lt;0.1 
               
               
                   
               
               
                 291 
                 pNOP211037 
                 KMT2D 
                 LKGMRRRSNSGEGARRANWRTCSLLTCRKPSLGRSCWT 
                 &lt;0.1 
               
               
                   
               
               
                 292 
                 pNOP211152 
                 KMT2D 
                 LPHILPGPPTAHRPQGRLEVQVVCVLYAVWGCFPWLPL 
                 &lt;0.1 
               
               
                   
               
               
                 293 
                 pNOP21288 
                 KMT2D 
                 SRRRARCLALTRLVSSSSSSHPRCPPKCLRRTPLDWPLPIPWSPASPRHRPPIPPILVLRGPLRSPR 
                 &lt;0.1 
               
               
                   
                   
                   
                 CWAPHLVLGLASQGNSTLPHLAPPDTSPPHLTHSSNPAAPRWITWLCLRALG 
                   
               
               
                   
               
               
                 294 
                 pNOP214330 
                 KMT2D 
                 TGFPQKNCPRWNPRTCSSSSRMFWALNENSIWVVEPLA 
                 &lt;0.1 
               
               
                   
               
               
                 295 
                 pNOP215253 
                 KMT2D 
                 WSPFLLSVRHSFSIPWFPKTPLLPSALLLPYHCPFPPR 
                 &lt;0.1 
               
               
                   
               
               
                 296 
                 pNOP215460 
                 KMT2D 
                 AAESRPDPLCWDTGQEQPCGVAPKQAEWPHPGARVLP 
                 &lt;0.1 
               
               
                   
               
               
                 297 
                 pNOP217529 
                 KMT2D 
                 GPAPSHPSRDPQTSGANLGAASWEGLTCCCPACRYLV 
                 &lt;0.1 
               
               
                   
               
               
                 298 
                 pNOP217538 
                 KMT2D 
                 GPFCSWGGPAKLWTRDPKSQGRWRLRKEGTPHIAERR 
                 &lt;0.1 
               
               
                   
               
               
                 299 
                 pNOP218359 
                 KMT2D 
                 ITARGGELSKLFIPLWAPPPYGAATHDQPHWLCPIRA 
                 &lt;0.1 
               
               
                   
               
               
                 300 
                 pNOP218743 
                 KMT2D 
                 KSTQWLSSTLAPSFGTRWPTGGRKSTKSRIEASTCSE 
                 &lt;0.1 
               
               
                   
               
               
                 301 
                 pNOP220563 
                 KMT2D 
                 QGSGTLGSPRQPSRNPEARAEQPGTWASGPGEWTGGA 
                 &lt;0.1 
               
               
                   
               
               
                 302 
                 pNOP223482 
                 KMT2D 
                 YSSGPTAATATFWWGWIPGWPFRGLLPWQPCSSKPRT 
                 &lt;0.1 
               
               
                   
               
               
                 303 
                 pNOP224854 
                 KMT2D 
                 EEEATAARAQEEQTGGHVPCLLAGSLLWEGAAGPEP 
                 &lt;0.1 
               
               
                   
               
               
                 304 
                 pNOP240334 
                 KMT2D 
                 WAAGIPGWAQGHFLAVGTQLRRPPLGPREDHQLTC 
                 &lt;0.1 
               
               
                   
               
               
                 305 
                 pNOP243509 
                 KMT2D 
                 GVSHAHSLCCCSQEPEWRDGGSGGAAEHEDPQLL 
                 &lt;0.1 
               
               
                   
               
               
                 306 
                 pNOP245157 
                 KMT2D 
                 LLTLIALPVRRRRKKMMTPCRIPWFSSPTQTNLS 
                 &lt;0.1 
               
               
                   
               
               
                 307 
                 pNOP248474 
                 KMT2D 
                 SPLSLSLVSRHPMGSTAILGPAPPWASLKAQTTQ 
                 &lt;0.1 
               
               
                   
               
               
                 308 
                 pNOP251217 
                 KMT2D 
                 CQCQFSWLRAPPGLSRPGGGWLPVHGVGGLYGC 
                 &lt;0.1 
               
               
                   
               
               
                 309 
                 pNOP257143 
                 KMT2D 
                 RFPSSSPQEMERSALEAASAAADHPEGQWAAGG 
                 &lt;0.1 
               
               
                   
               
               
                 310 
                 pNOP257396 
                 KMT2D 
                 RLPCAPGPRGAGPCDPYGGLPRMQADSRAGLTM 
                 &lt;0.1 
               
               
                   
               
               
                 311 
                 pNOP257632 
                 KMT2D 
                 RRKSLGHPLLAMGPQTWALLTHPPQAPTWVAWS 
                 &lt;0.1 
               
               
                   
               
               
                 312 
                 pNOP258695 
                 KMT2D 
                 STPLAVPDQSLKSSHTTNAFSHPLSHLILTTTL 
                 &lt;0.1 
               
               
                   
               
               
                 313 
                 pNOP259446 
                 KMT2D 
                 VGSMEGRQAWYPSRAHSQCYHRSPWAPCHLPCA 
                 &lt;0.1 
               
               
                   
               
               
                 314 
                 pNOP261027 
                 KMT2D 
                 CHCPLSRGLRGHAHLLEPPHQQSSLLLSLFYW 
                 &lt;0.1 
               
               
                   
               
               
                 315 
                 pNOP261872 
                 KMT2D 
                 EGLLWGHGRTTSSPADPQPTEWPRRILPAGKV 
                 &lt;0.1 
               
               
                   
               
               
                 316 
                 pNOP264714 
                 KMT2D 
                 LHTLWALCQPGDLPYLSCSLRRRGPTNPVPPL 
                 &lt;0.1 
               
               
                   
               
               
                 317 
                 pNOP270434 
                 KMT2D 
                 AAAQCTERTGTWGHSVSWSGPTSETPFLPCK 
                 &lt;0.1 
               
               
                   
               
               
                 318 
                 pNOP276046 
                 KMT2D 
                 MPSLGTQCHQSSPFPNGGPFLPRPQPCPSPG 
                 &lt;0.1 
               
               
                   
               
               
                 319 
                 pNOP277209 
                 KMT2D 
                 PVLLYQLWASLSRGLPGHCSDCPQTCWLAVP 
                 &lt;0.1 
               
               
                   
               
               
                 320 
                 pNOP277754 
                 KMT2D 
                 RARCSVRCMPRAAKGWARDLYATQGTRAPAM 
                 &lt;0.1 
               
               
                   
               
               
                 321 
                 pNOP279143 
                 KMT2D 
                 SKSSSRAWRTWSSLTPLPRPCGIASLSLWLP 
                 &lt;0.1 
               
               
                   
                   
                   
                 PQGTSTHRAAPWGPAAGPQGRAMGCPHYALRRFCHHLHPTDPSPTCPMEPHSDQASPLLSKSEKTQ 
                   
               
               
                   
               
               
                 322 
                 pNOP28077 
                 KMT2D 
                 GLEWVALWRQLNSQVPRTQACPALAKQSWRSNGSASDYESC 
                 &lt;0.1 
               
               
                   
               
               
                 323 
                 pNOP284778 
                 KMT2D 
                 HHSAGRTAAHVPCGGPCVPRHRTAAASPDG 
                 &lt;0.1 
               
               
                   
               
               
                 324 
                 pNOP285042 
                 KMT2D 
                 IEQQSSSNTPHQGSYPANWFGAGQPAPVEH 
                 &lt;0.1 
               
               
                   
               
               
                 325 
                 pNOP287872 
                 KMT2D 
                 PLCPLWQWLPSQWAEPAEGGLWKWGAAHWP 
                 &lt;0.1 
               
               
                   
                   
                   
                 GQGLDLRAHPGSLPHQEPYLQDQSLALSIPHLHHPALKSQRDLHNYLPPAPSFPLRPSSLPPIQGPP 
                   
               
               
                   
                   
                   
                 NLR 
                   
               
               
                   
               
               
                 326 
                 pNOP29324 
                 KMT2D 
                 GQPWSRLLGGSHLLLPSLQIPCLARVWDLGIPQTT 
                 &lt;0.1 
               
               
                   
               
               
                 327 
                 pNOP298931 
                 KMT2D 
                 NHPWRNCLLTLGSARRAGCAGPVGRAQQN 
                 &lt;0.1 
               
               
                   
               
               
                 328 
                 pNOP302234 
                 KMT2D 
                 SPHSLGTHNSCLSNPSPSLSPALCSCSHL 
                 &lt;0.1 
               
               
                   
               
               
                 329 
                 pNOP303477 
                 KMT2D 
                 VAPSWGQGPSLAMTDSPGHLHQPRLPLWM 
                 &lt;0.1 
               
               
                   
               
               
                 330 
                 pNOP310713 
                 KMT2D 
                 MDRWCLRHPNSASSRNLGKSHVPWEPSQ 
                 &lt;0.1 
               
               
                   
               
               
                 331 
                 pNOP318057 
                 KMT2D 
                 CHQIPFLLHSHPSSQLRPHRPCLLWGS 
                 &lt;0.1 
               
               
                   
               
               
                 332 
                 pNOP318220 
                 KMT2D 
                 CPPSHQLMPSSNAWLHPWLWCPIKGIC 
                 &lt;0.1 
               
               
                   
               
               
                 333 
                 pNOP318964 
                 KMT2D 
                 EAQAGYRAAEQDPETTGSGPETAEGAH 
                 &lt;0.1 
               
               
                   
               
               
                 334 
                 pNOP323435 
                 KMT2D 
                 LNHCPGWRAVKTIYSAMGATPLWSCHS 
                 &lt;0.1 
               
               
                   
               
               
                 335 
                 pNOP323658 
                 KMT2D 
                 LRQDFHRRTAQDGIQGPAAALQGCSGL 
                 &lt;0.1 
               
               
                   
               
               
                 336 
                 pNOP324899 
                 KMT2D 
                 PADTTLVAAPHPTPIGAAEDGEWRHPI 
                 &lt;0.1 
               
               
                   
               
               
                 337 
                 pNOP325001 
                 KMT2D 
                 PDHVTTAQAAPTARTAWPPRRGRIGGF 
                 &lt;0.1 
               
               
                   
               
               
                 338 
                 pNOP325387 
                 KMT2D 
                 PMTISLILRTISTRSPATVEPGIVGNG 
                 &lt;0.1 
               
               
                   
               
               
                 339 
                 pNOP325875 
                 KMT2D 
                 PWSPGSNPPPDGQGTKHRRPSRFFRGH 
                 &lt;0.1 
               
               
                   
               
               
                 340 
                 pNOP334374 
                 KMT2D 
                 GLTCFPTTGGLAHVPAAGGVTPVATT 
                 &lt;0.1 
               
               
                   
               
               
                 341 
                 pNOP341158 
                 KMT2D 
                 RSLLSPPILASLPPLAVAAQSMGRAS 
                 &lt;0.1 
               
               
                   
               
               
                 342 
                 pNOP343442 
                 KMT2D 
                 TWTWTCGCTSTVPFGPRRCMRPRAGH 
                 &lt;0.1 
               
               
                   
               
               
                 343 
                 pNOP344075 
                 KMT2D 
                 WACPSAEPGPGPVGAPQLCPLVHGGV 
                 &lt;0.1 
               
               
                   
               
               
                 344 
                 pNOP356926 
                 KMT2D 
                 SQARLPRLVKPLQTNHEALEKGSSS 
                 &lt;0.1 
               
               
                   
               
               
                 345 
                 pNOP362881 
                 KMT2D 
                 FWESQASGDSSGLQWGSGAALCSL 
                 &lt;0.1 
               
               
                   
               
               
                 346 
                 pNOP363170 
                 KMT2D 
                 GGPLEVGRCPLALTTIPSCLPRIT 
                 &lt;0.1 
               
               
                   
               
               
                 347 
                 pNOP363905 
                 KMT2D 
                 GWVSSPHFAGGWGVPSSPARGASR 
                 &lt;0.1 
               
               
                   
               
               
                 348 
                 pNOP364735 
                 KMT2D 
                 IITFFSTGGVALVSTGRVTPISCT 
                 &lt;0.1 
               
               
                   
                   
                   
                 GPYTCPPRRTWRVLLGSPLVCCMVGRRMGAGGPRTMWCGQGHLLRDLTALLPLHQARCLHPLPLT 
                   
               
               
                   
               
               
                 349 
                 pNOP36658 
                 KMT2D 
                 WMSTALPLPLRDCQRFLPIHENTAAAMPRAQ 
                 &lt;0.1 
               
               
                   
               
               
                 350 
                 pNOP370861 
                 KMT2D 
                 RMMKSLLTWVWVWMWPRVMMNLAP 
                 &lt;0.1 
               
               
                   
                   
                   
                 GISEHLHRRDQHPLQQAVCALQVISVPAAAHRMEEQRVPGSLPYPGPGALCSQGPRKAHNGYRVHW 
                   
               
               
                   
               
               
                 351 
                 pNOP37587 
                 KMT2D 
                 HHHSERGGQPAGENLRRAESRHLHVPNKQ 
                 &lt;0.1 
               
               
                   
               
               
                 352 
                 pNOP378675 
                 KMT2D 
                 GAALVPSPWGTILISLAWRASPV 
                 &lt;0.1 
               
               
                   
               
               
                 353 
                 pNOP378896 
                 KMT2D 
                 GFQDNSSSKLACSTQQVEEAMGS 
                 &lt;0.1 
               
               
                   
               
               
                 354 
                 pNOP386633 
                 KMT2D 
                 RHPQCPVTLRSQAPQVKGCLALT 
                 &lt;0.1 
               
               
                   
               
               
                 355 
                 pNOP388467 
                 KMT2D 
                 SMKLTSGSMRSGCSIPSSSYRCS 
                 &lt;0.1 
               
               
                   
               
               
                 356 
                 pNOP390234 
                 KMT2D 
                 VEARPPLLGHRTRAALWGCPQAS 
                 &lt;0.1 
               
               
                   
               
               
                 357 
                 pNOP394670 
                 KMT2D 
                 EQRAAGVCNQSHRAGPGGPGLH 
                 &lt;0.1 
               
               
                   
               
               
                 358 
                 pNOP404863 
                 KMT2D 
                 RTGRATCTGGPHTTHSHQIRHR 
                 &lt;0.1 
               
               
                   
               
               
                 359 
                 pNOP405923 
                 KMT2D 
                 SPRWRRVDATLLLANSPLLPPR 
                 &lt;0.1 
               
               
                   
               
               
                 360 
                 pNOP406378 
                 KMT2D 
                 STPLAVPDQSLKSSHTTNGPIP 
                 &lt;0.1 
               
               
                   
               
               
                 361 
                 pNOP408074 
                 KMT2D 
                 VTRRHHPRRCPPPHPHRCSRRW 
                 &lt;0.1 
               
               
                   
               
               
                 362 
                 pNOP410165 
                 KMT2D 
                 AVDHLLRPHLCPTCWLSPLFP 
                 &lt;0.1 
               
               
                   
               
               
                 363 
                 pNOP412059 
                 KMT2D 
                 ELLSLSPLSQSPGRSDYPLRC 
                 &lt;0.1 
               
               
                   
               
               
                 364 
                 pNOP413106 
                 KMT2D 
                 GEAKLPSPCSRPHLLGSPGRP 
                 &lt;0.1 
               
               
                   
               
               
                 365 
                 pNOP414691 
                 KMT2D 
                 HLTKRTKSSSSPAGESPKERS 
                 &lt;0.1 
               
               
                   
               
               
                 366 
                 pNOP421083 
                 KMT2D 
                 QRGQNHHHLQPANPQRRGANL 
                 &lt;0.1 
               
               
                   
               
               
                 367 
                 pNOP421373 
                 KMT2D 
                 RASGPGGIRSSPTETLSPTGP 
                 &lt;0.1 
               
               
                   
               
               
                 368 
                 pNOP425823 
                 KMT2D 
                 TWPPSPRFPVGGNFHPSARPW 
                 &lt;0.1 
               
               
                   
               
               
                 369 
                 pNOP43053 
                 KMT2D 
                 PLGVWHYLDSLVAPSLIQLWPNSSNSNILVGLDPWLALQGASSLATLLFEASDLIQGFYRKGSCSCS 
                 &lt;0.1 
               
               
                   
                   
                   
                 SNVCSWPRNCSSSSSSNSSSSTF 
                   
               
               
                   
               
               
                 370 
                 pNOP438522 
                 KMT2D 
                 PAALPGTLTIPVPLTVWPKS 
                 &lt;0.1 
               
               
                   
                   
                   
                 ALSPWALYSSFSSSSSCNSNSNFSSSSSSSYNSNSNFSSNSFNSSNSSSSFNNSSSNSFNSSNSSYN 
                   
               
               
                   
                   
                   
                 SNSN 
                   
               
               
                   
               
               
                 371 
                 pNOP44778 
                 KMT2D 
                 NNSSSFNSSSNSSRWAF 
                 &lt;0.1 
               
               
                   
               
               
                 372 
                 pNOP458695 
                 KMT2D 
                 PAPHSRWRKPWAARQWIIF 
                 &lt;0.1 
               
               
                   
               
               
                 373 
                 pNOP465144 
                 KMT2D 
                 TQPFLQRPLRGPLHIREGR 
                 &lt;0.1 
               
               
                   
               
               
                 374 
                 pNOP466225 
                 KMT2D 
                 VSEGRGALWADGACRASHS 
                 &lt;0.1 
               
               
                   
                   
                   
                 PASYPCSLRTCWSMRRRSCRRSSSFQHSCSLPSSSSNSSSSIPYCLHQALPRPCLCHMRALLPVWLG 
                   
               
               
                   
                   
                   
                 PNS 
                   
               
               
                   
               
               
                 375 
                 pNOP46646 
                 KMT2D 
                 SFPWVLQVPDSQVCPSH 
                 &lt;0.1 
               
               
                   
               
               
                 376 
                 pNOP468251 
                 KMT2D 
                 APERSCGRRTGSGPARPC 
                 &lt;0.1 
               
               
                   
               
               
                 377 
                 pNOP473253 
                 KMT2D 
                 GSWWEGKGSGRQEPRHWP 
                 &lt;0.1 
               
               
                   
               
               
                 378 
                 pNOP481442 
                 KMT2D 
                 QKPRSQSRAAWYLGIWTR 
                 &lt;0.1 
               
               
                   
               
               
                 379 
                 pNOP483870 
                 KMT2D 
                 RTLPAPFPLGTFSCQSPY 
                 &lt;0.1 
               
               
                   
               
               
                 380 
                 pNOP487229 
                 KMT2D 
                 VAQEDPPCWKSLSSRVGL 
                 &lt;0.1 
               
               
                   
               
               
                 381 
                 pNOP487911 
                 KMT2D 
                 VTVGCPHPGDTHQPSTRS 
                 &lt;0.1 
               
               
                   
               
               
                 382 
                 pNOP490152 
                 KMT2D 
                 AREWGFDLAWWTCSIWG 
                 &lt;0.1 
               
               
                   
               
               
                 383 
                 pNOP490194 
                 KMT2D 
                 ARQDGELTGSQRVTPAH 
                 &lt;0.1 
               
               
                   
               
               
                 384 
                 pNOP493996 
                 KMT2D 
                 GAATLPPVRGAAPVTPA 
                 &lt;0.1 
               
               
                   
               
               
                 385 
                 pNOP494542 
                 KMT2D 
                 GIAPIPPACGVTPVSTA 
                 &lt;0.1 
               
               
                   
               
               
                 386 
                 pNOP494543 
                 KMT2D 
                 GIAPVPAAGGIAPLSAA 
                 &lt;0.1 
               
               
                   
               
               
                 387 
                 pNOP501743 
                 KMT2D 
                 NPHTLQTAPYPEQHQHV 
                 &lt;0.1 
               
               
                   
               
               
                 388 
                 pNOP502714 
                 KMT2D 
                 PLCNPRNQGPCNVKPNH 
                 &lt;0.1 
               
               
                   
               
               
                 389 
                 pNOP506673 
                 KMT2D 
                 RVTHVSTTGGISSVPTI 
                 &lt;0.1 
               
               
                   
               
               
                 390 
                 pNOP507548 
                 KMT2D 
                 SLPASSQPAHFCSGSDQ 
                 &lt;0.1 
               
               
                   
               
               
                 391 
                 pNOP508277 
                 KMT2D 
                 SSQQPYEAPYPEQHQHV 
                 &lt;0.1 
               
               
                   
               
               
                 392 
                 pNOP512482 
                 KMT2D 
                 AGSGRVYGAAWHSLAT 
                 &lt;0.1 
               
               
                   
               
               
                 393 
                 pNOP513338 
                 KMT2D 
                 AVRPFLQLGWAGQALD 
                 &lt;0.1 
               
               
                   
               
               
                 394 
                 pNOP513379 
                 KMT2D 
                 AWPPQSSGPGSWEVAL 
                 &lt;0.1 
               
               
                   
               
               
                 395 
                 pNOP513605 
                 KMT2D 
                 CGAWQRGDRGKQKTQA 
                 &lt;0.1 
               
               
                   
               
               
                 396 
                 pNOP514247 
                 KMT2D 
                 CSGFTARAWTDPWQFG 
                 &lt;0.1 
               
               
                   
               
               
                 397 
                 pNOP517078 
                 KMT2D 
                 GALYTSGRAVSNRNYP 
                 &lt;0.1 
               
               
                   
               
               
                 398 
                 pNOP518512 
                 KMT2D 
                 GVGPAVHHLTCALCQH 
                 &lt;0.1 
               
               
                   
               
               
                 399 
                 pNOP522295 
                 KMT2D 
                 LAPVSSGVPWGEPRAQ 
                 &lt;0.1 
               
               
                   
               
               
                 400 
                 pNOP523824 
                 KMT2D 
                 LTLLRHPPGWPGVKDT 
                 &lt;0.1 
               
               
                   
                   
                   
                 SHGRISEQAAATTAAAAATTATALSCAGSQPFPESPAAHQAPWSAAPWPWAAATTGASGWASRRSS 
                   
               
               
                   
               
               
                 401 
                 pNOP52423 
                 KMT2D 
                 PDPWGYGTTWTAWWPLP 
                 &lt;0.1 
               
               
                   
               
               
                 402 
                 pNOP526117 
                 KMT2D 
                 PICSAPIDSSAPTSAP 
                 &lt;0.1 
               
               
                   
               
               
                 403 
                 pNOP530549 
                 KMT2D 
                 SAEPCGSWEWPGAECW 
                 &lt;0.1 
               
               
                   
               
               
                 404 
                 pNOP530881 
                 KMT2D 
                 SFPHLQAPQWGRLLPS 
                 &lt;0.1 
               
               
                   
               
               
                 405 
                 pNOP537026 
                 KMT2D 
                 ALLLSSGGSTLSGTR 
                 &lt;0.1 
               
               
                   
               
               
                 406 
                 pNOP548556 
                 KMT2D 
                 LRGAQSTRAAGATAL 
                 &lt;0.1 
               
               
                   
               
               
                 407 
                 pNOP548811 
                 KMT2D 
                 LTIVRCWDSYQRRQS 
                 &lt;0.1 
               
               
                   
               
               
                 408 
                 pNOP550374 
                 KMT2D 
                 NPHTLQTRFHIHYLI 
                 &lt;0.1 
               
               
                   
               
               
                 409 
                 pNOP55230 
                 KMT2D 
                 QQAGWAGAETTGYPQQQGGCSSKEAFDTEAQAGTEGKRQVGELPKEAAEGGRGQGQRGLAETAET 
                 &lt;0.1 
               
               
                   
                   
                   
                 GAVPAAPNGACYHRQF 
                   
               
               
                   
               
               
                 410 
                 pNOP558727 
                 KMT2D 
                 TGGPAAGGGARTLGP 
                 &lt;0.1 
               
               
                   
                   
                   
                 DRWQSSSNSSRVLEYRQTKLWVPSPRALCLPAATKASWSSSCPLNHPRGPRACWALPRWLCCSSSTLE 
                   
               
               
                   
               
               
                 411 
                 pNOP56040 
                 KMT2D 
                 LWAPRALTDRCL 
                 &lt;0.1 
               
               
                   
               
               
                 412 
                 pNOP563434 
                 KMT2D 
                 ARAELFCCLPAGLH 
                 &lt;0.1 
               
               
                   
               
               
                 413 
                 pNOP566785 
                 KMT2D 
                 EPDQQADQGGRHSP 
                 &lt;0.1 
               
               
                   
               
               
                 414 
                 pNOP568806 
                 KMT2D 
                 GKQGSNLSPSWRPP 
                 &lt;0.1 
               
               
                   
               
               
                 415 
                 pNOP569843 
                 KMT2D 
                 GVWPGLRPLTPAAL 
                 &lt;0.1 
               
               
                   
               
               
                 416 
                 pNOP570795 
                 KMT2D 
                 HRSPSGYRRQATGW 
                 &lt;0.1 
               
               
                   
               
               
                 417 
                 pNOP573651 
                 KMT2D 
                 KSQSPSTFASKVCG 
                 &lt;0.1 
               
               
                   
               
               
                 418 
                 pNOP575068 
                 KMT2D 
                 LLWPRGRHSPSGWD 
                 &lt;0.1 
               
               
                   
               
               
                 419 
                 pNOP580906 
                 KMT2D 
                 RACSPGSGCGCGQG 
                 &lt;0.1 
               
               
                   
               
               
                 420 
                 pNOP580931 
                 KMT2D 
                 RAGGAPQGCCLCPG 
                 &lt;0.1 
               
               
                   
               
               
                 421 
                 pNOP581766 
                 KMT2D 
                 RIPWPRGQSRYTRT 
                 &lt;0.1 
               
               
                   
               
               
                 422 
                 pNOP584053 
                 KMT2D 
                 SFLPITRYPSLPVP 
                 &lt;0.1 
               
               
                   
                   
                   
                 SKSLASFSGENGCTCSVWGALCSTPSDSCCLTRWLTFIVPLPSIPWATRPRASIGASAPTIVAAAIA 
                   
               
               
                   
                   
                   
                 VLLV 
                   
               
               
                   
               
               
                 423 
                 pNOP58594 
                 KMT2D 
                 RTTGGRSL 
                 &lt;0.1 
               
               
                   
               
               
                 424 
                 pNOP588394 
                 KMT2D 
                 VRPAQPTCGRGLCP 
                 &lt;0.1 
               
               
                   
               
               
                 425 
                 pNOP589969 
                 KMT2D 
                 YLLTCLQRAPWSRA 
                 &lt;0.1 
               
               
                   
               
               
                 426 
                 pNOP591792 
                 KMT2D 
                 ATRPLTSATGLIP 
                 &lt;0.1 
               
               
                   
               
               
                 427 
                 pNOP594808 
                 KMT2D 
                 EKRLTCCDSSLSI 
                 &lt;0.1 
               
               
                   
               
               
                 428 
                 pNOP594895 
                 KMT2D 
                 ELPLSQWPLNQER 
                 &lt;0.1 
               
               
                   
               
               
                 429 
                 pNOP595078 
                 KMT2D 
                 EPLHRGRCGAGSR 
                 &lt;0.1 
               
               
                   
               
               
                 430 
                 pNOP596763 
                 KMT2D 
                 GGCISGGGSLCSV 
                 &lt;0.1 
               
               
                   
               
               
                 431 
                 pNOP607374 
                 KMT2D 
                 PGSSPHQQGAEAG 
                 &lt;0.1 
               
               
                   
               
               
                 432 
                 pNOP608986 
                 KMT2D 
                 QGTARHASLLFLS 
                 &lt;0.1 
               
               
                   
                   
                   
                 ENLEGPAGLTIGVLHGRQAYGGRRAQNYVVWTRPSSQGSHSAAPTAPGSVPPSLAAHLDVHGFTTSP 
                   
               
               
                   
               
               
                 433 
                 pNOP60941 
                 KMT2D 
                 ARLPAVPSYP 
                 &lt;0.1 
               
               
                   
               
               
                 434 
                 pNOP614310 
                 KMT2D 
                 SLWRLLHLQSWCP 
                 &lt;0.1 
               
               
                   
               
               
                 435 
                 pNOP621656 
                 KMT2D 
                 ASAWSSWSCPVH 
                 &lt;0.1 
               
               
                   
               
               
                 436 
                 pNOP626830 
                 KMT2D 
                 GAVPREPRPGRH 
                 &lt;0.1 
               
               
                   
                   
                   
                 GIPTQHQAGTSGRAMCPGSPVSEEGGQWGANRGTRNQQPPPAGRPSLRSWASALAEATPGKECAT 
                   
               
               
                   
               
               
                 437 
                 pNOP62730 
                 KMT2D 
                 QHWAGVRGAAS 
                 &lt;0.1 
               
               
                   
               
               
                 438 
                 pNOP636166 
                 KMT2D 
                 MQSVPSLQETWE 
                 &lt;0.1 
               
               
                   
               
               
                 439 
                 pNOP637952 
                 KMT2D 
                 PACRGRRGAELS 
                 &lt;0.1 
               
               
                   
               
               
                 440 
                 pNOP638098 
                 KMT2D 
                 PCLVDLQHLGMS 
                 &lt;0.1 
               
               
                   
               
               
                 441 
                 pNOP638632 
                 KMT2D 
                 PLFSPTLTPSVP 
                 &lt;0.1 
               
               
                   
               
               
                 442 
                 pNOP640173 
                 KMT2D 
                 QIFTPRAWRYPH 
                 &lt;0.1 
               
               
                   
               
               
                 443 
                 pNOP643882 
                 KMT2D 
                 RTGPAKVNCFFH 
                 &lt;0.1 
               
               
                   
               
               
                 444 
                 pNOP645741 
                 KMT2D 
                 SPHLLPIPLAWG 
                 &lt;0.1 
               
               
                   
               
               
                 445 
                 pNOP648045 
                 KMT2D 
                 TPRYPGPRHVRP 
                 &lt;0.1 
               
               
                   
               
               
                 446 
                 pNOP652166 
                 KMT2D 
                 AGHWGQEGYLQ 
                 &lt;0.1 
               
               
                   
               
               
                 447 
                 pNOP654960 
                 KMT2D 
                 CYVDRRPCQVH 
                 &lt;0.1 
               
               
                   
               
               
                 448 
                 pNOP660899 
                 KMT2D 
                 GWGREGIPSAQ 
                 &lt;0.1 
               
               
                   
               
               
                 449 
                 pNOP663294 
                 KMT2D 
                 ISPTQAPCPAP 
                 &lt;0.1 
               
               
                   
               
               
                 450 
                 pNOP671528 
                 KMT2D 
                 PIPQTPLPLAG 
                 &lt;0.1 
               
               
                   
               
               
                 451 
                 pNOP672236 
                 KMT2D 
                 PRTFWAPNSPC 
                 &lt;0.1 
               
               
                   
               
               
                 452 
                 pNOP675830 
                 KMT2D 
                 RLSPGRVESHH 
                 &lt;0.1 
               
               
                   
               
               
                 453 
                 pNOP679479 
                 KMT2D 
                 SQTTRESRGPT 
                 &lt;0.1 
               
               
                   
               
               
                 454 
                 pNOP679892 
                 KMT2D 
                 SSLMQCCLAIP 
                 &lt;0.1 
               
               
                   
               
               
                 455 
                 pNOP682972 
                 KMT2D 
                 VGMGSPTRVRR 
                 &lt;0.1 
               
               
                   
               
               
                 456 
                 pNOP684498 
                 KMT2D 
                 WLRAALGWHLV 
                 &lt;0.1 
               
               
                   
                   
                   
                 PTLPATSTSHAFLYGCEQPATGRRLPSFLSASTLSWVPALTAATATTVAATTGNSSNLHAICHVSSL 
                   
               
               
                   
                   
                   
                 SINS 
                   
               
               
                   
               
               
                 457 
                 pNOP68935 
                 KMT2D 
                 WT 
                 &lt;0.1 
               
               
                   
                   
                   
                 ACPPYDPSPISRLPSGAGFSHPDGAPSSSVFATPSAFPGSPKLPSFPVLSSCPTTVRSLPVESHREG 
                   
               
               
                   
                   
                   
                 SGGL 
                   
               
               
                   
               
               
                 458 
                 pNOP69709 
                 KMT2D 
                 R 
                 &lt;0.1 
               
               
                   
                   
                   
                 HHAEYRGSLLQHRQICPNAGHVCGMWQLWPGGRGPPPCLFAVLSVLSPLLCQQQDHQGDAAQGLA 
                   
               
               
                   
               
               
                 459 
                 pNOP70346 
                 KMT2D 
                 LCGVYCV 
                 &lt;0.1 
               
               
                   
               
               
                 460 
                 pNOP704364 
                 KMT2D 
                 MWRLPCTEDC 
                 &lt;0.1 
               
               
                   
               
               
                 461 
                 pNOP706242 
                 KMT2D 
                 PAESSALGEG 
                 &lt;0.1 
               
               
                   
               
               
                 462 
                 pNOP708910 
                 KMT2D 
                 QKLAWPCCVT 
                 &lt;0.1 
               
               
                   
               
               
                 463 
                 pNOP709657 
                 KMT2D 
                 QSPLPAKGQR 
                 &lt;0.1 
               
               
                   
               
               
                 464 
                 pNOP713389 
                 KMT2D 
                 RWCGAHGVRN 
                 &lt;0.1 
               
               
                   
               
               
                 465 
                 pNOP715424 
                 KMT2D 
                 SQLLLPLRLW 
                 &lt;0.1 
               
               
                   
               
               
                 466 
                 pNOP718753 
                 KMT2D 
                 TWHLRKPGDQ 
                 &lt;0.1 
               
               
                   
                   
                   
                 EHLGGGGPSFPSSGLRPVGARGPGPLPCHPPHSSGQHPSLPRYQTLWGPWPGGPWKAACHNLGKG 
                   
               
               
                   
               
               
                 467 
                 pNOP78569 
                 KMT2D 
                 QRK 
                 &lt;0.1 
               
               
                   
               
               
                 468 
                 pNOP81414 
                 KMT2D 
                 IPTRSGLRTTLSVTAVTKPREVRLSAPLLSSIPRCVADFHPQSLAIPPLTSPMLCTLHAKGSQRVGT 
                 &lt;0.1 
               
               
                   
               
               
                 469 
                 pNOP85659 
                 KMT2D 
                 AWGTTSVPSARGAAVVPIWGAILVASADATRSPSSSTLTHHHSCGPTGPVSFGGVRVPLWCQRGQ 
                 &lt;0.1 
               
               
                   
               
               
                 470 
                 pNOP85855 
                 KMT2D 
                 DPGRGTDECGGCPAPRTANQVLPVPANWCHQQLQSHALPQCLPFCLCHPCQVHVLQGQDHAVSNA 
                 &lt;0.1 
               
               
                   
               
               
                 471 
                 pNOP96015 
                 KMT2D 
                 VLSSSSSYRHSSCSGSCSRVRQYARPHPTRSLGPRPLPSRASWAANLNLGASLDHRQAPSRS 
                 &lt;0.1 
               
               
                   
               
               
                 472 
                 pNOP98767 
                 KMT2D 
                 TAPACLRHIRAPSQARPTPPTASSLCTPSHLSTGGCAPNGRTTCTWLAPVSRAWGSMQPRT 
                 &lt;0.1 
               
               
                   
               
               
                 473 
                 pNOP259159 
                 PIK3R1 
                 TRPYPAEKDERPILDVVDSKRCSAKEVERVVGQ 
                 2.08 
               
               
                   
               
               
                 474 
                 pNOP252683 
                 PIK3R1 
                 GKNYMNITLSFKKKVENMIDYMKNIPAHPRKSK 
                 1.13 
               
               
                   
               
               
                 475 
                 pNOP211670 
                 PIK3R1 
                 NILEGKKSRLPHQSPGHLGLFLLHQVLRKLKQMLNNKL 
                 0.38 
               
               
                   
               
               
                 476 
                 pNOP310780 
                 PIK3R1 
                 MKNFEIQQTGPFWYEMRLLKCMVIILLH 
                 0.38 
               
               
                   
                   
                   
                 TSGWAMKTLKTNIHWWKMMKICPIMMRRHGMLEAATETKLKTCCEGSEMALFLSGRAVNRAAMP 
                   
               
               
                   
               
               
                 477 
                 pNOP85148 
                 PIK3R1 
                 AL 
                 0.38 
               
               
                   
               
               
                 478 
                 pNOP176901 
                 PIK3R1 
                 NHRGKGGLSGNLRRIYWKEKNLASHTKAPATSASSCCTRFFEN 
                 0.19 
               
               
                   
               
               
                 479 
                 pNOP269023 
                 PIK3R1 
                 TGLLCLLCSGGRRSKALCHKQNSNWLWLCRAL 
                 0.19 
               
               
                   
               
               
                 480 
                 pNOP350339 
                 PIK3R1 
                 KERSGMFNSIQNTELQQPGRITTAS 
                 0.19 
               
               
                   
               
               
                 481 
                 pNOP401447 
                 PIK3R1 
                 NYFIQYPNTNRIKLSKKIILKL 
                 0.19 
               
               
                   
               
               
                 482 
                 pNOP498354 
                 PIK3R1 
                 KPVAREARWHFSCPGEQ 
                 0.19 
               
               
                   
               
               
                 483 
                 pNOP498791 
                 PIK3R1 
                 KTSRYSRRDLFGTRCVY 
                 0.19 
               
               
                   
               
               
                 484 
                 pNOP528940 
                 PIK3R1 
                 RIYPHIPGNPNEKDSY 
                 0.19 
               
               
                   
               
               
                 485 
                 pNOP556984 
                 PIK3R1 
                 SKYFIEMGNMASLTH 
                 0.19 
               
               
                   
               
               
                 486 
                 pNOP696809 
                 PIK3R1 
                 HSVSRKKSRI 
                 0.19 
               
               
                   
               
               
                 487 
                 pNOP94837 
                 PIK3R1 
                 LSRILQSSLPLLTLPRLFLSSSWKPLKRKVWNVQLYTEHRAPATWQNYDSFLIVIHPPWTWK 
                 0.19 
               
               
                   
               
               
                 488 
                 pNOP126105 
                 PIK3R1 
                 LVQLSERTGATLPTHLPCAAQRLPQCHTSLPSICTAEAMKRLLFDPSPEVQPP 
                 &lt;0.1 
               
               
                   
               
               
                 489 
                 pNOP204353 
                 PIK3R1 
                 NVQYCLEYGRPGFRICQDRYKLWHRLDVLYRNGPTSTAS 
                 &lt;0.1 
               
               
                   
               
               
                 490 
                 pNOP243907 
                 PIK3R1 
                 HTSSVLAYASVFVKTFLQALSNLQQKSVECKSTL 
                 &lt;0.1 
               
               
                   
               
               
                 491 
                 pNOP280681 
                 PIK3R1 
                 VTIPYSKRTSSEPQAGKSFDSPGSCRAVCPS 
                 &lt;0.1 
               
               
                   
               
               
                 492 
                 pNOP302169 
                 PIK3R1 
                 SMCTFWLTLSNAISWTYQILSFQQPFTVK 
                 &lt;0.1 
               
               
                   
               
               
                 493 
                 pNOP316041 
                 PIK3R1 
                 VLRGTSTERCMIIKRKEKKILTCTWVTY 
                 &lt;0.1 
               
               
                   
               
               
                 494 
                 pNOP324179 
                 PIK3R1 
                 MQEYSLKFSALCFSDSQQPALIILKTS 
                 &lt;0.1 
               
               
                   
               
               
                 495 
                 pNOP388646 
                 PIK3R1 
                 SQIGCEITLSSIQIPTGSSCQRR 
                 &lt;0.1 
               
               
                   
               
               
                 496 
                 pNOP388654 
                 PIK3R1 
                 SQLNGMNDSLHQHCLLNHQNLLL 
                 &lt;0.1 
               
               
                   
               
               
                 497 
                 pNOP398534 
                 PIK3R1 
                 KNWCYITNTPPLCSTTTPSMSH 
                 &lt;0.1 
               
               
                   
               
               
                 498 
                 pNOP400742 
                 PIK3R1 
                 NDFFSSRSTKLRRIYSAIEEAY 
                 &lt;0.1 
               
               
                   
               
               
                 499 
                 pNOP410978 
                 PIK3R1 
                 CVSYYSLQQKNLIRTAGWKEL 
                 &lt;0.1 
               
               
                   
               
               
                 500 
                 pNOP416624 
                 PIK3R1 
                 KSLNVKAMRKKYKGLCIIMIS 
                 &lt;0.1 
               
               
                   
               
               
                 501 
                 pNOP434360 
                 PIK3R1 
                 ITICPYKMLNGTGEISRGKK 
                 &lt;0.1 
               
               
                   
               
               
                 502 
                 pNOP440919 
                 PIK3R1 
                 RFQTLSPGLTKSCHSSSRLQ 
                 &lt;0.1 
               
               
                   
               
               
                 503 
                 pNOP442163 
                 PIK3R1 
                 RSLLGRLAYLISIGLRFSIC 
                 &lt;0.1 
               
               
                   
               
               
                 504 
                 pNOP486435 
                 PIK3R1 
                 TKQQLAMALPSPITCTAL 
                 &lt;0.1 
               
               
                   
               
               
                 505 
                 pNOP498941 
                 PIK3R1 
                 KYLKNSARPKSGTAKNT 
                 &lt;0.1 
               
               
                   
               
               
                 506 
                 pNOP499619 
                 PIK3R1 
                 LLDSVMDRKPGLKKLAG 
                 &lt;0.1 
               
               
                   
               
               
                 507 
                 pNOP500601 
                 PIK3R1 
                 MAIMKPQGKGGTFRELT 
                 &lt;0.1 
               
               
                   
               
               
                 508 
                 pNOP506595 
                 PIK3R1 
                 RTVPDPRAVQQRIHRKV 
                 &lt;0.1 
               
               
                   
               
               
                 509 
                 pNOP507482 
                 PIK3R1 
                 SLESVKLLTVEEDWKKT 
                 &lt;0.1 
               
               
                   
               
               
                 510 
                 pNOP513755 
                 PIK3R1 
                 CITCKHCLLNHQNLLL 
                 &lt;0.1 
               
               
                   
               
               
                 511 
                 pNOP514604 
                 PIK3R1 
                 DDSFDSPGSCRAVCPS 
                 &lt;0.1 
               
               
                   
               
               
                 512 
                 pNOP522199 
                 PIK3R1 
                 KWTHQHCLLNHQNLLL 
                 &lt;0.1 
               
               
                   
               
               
                 513 
                 pNOP533872 
                 PIK3R1 
                 TTSFDSPGSCRAVCPS 
                 &lt;0.1 
               
               
                   
               
               
                 514 
                 pNOP552207 
                 PIK3R1 
                 PTQYMHSRGDEALTL 
                 &lt;0.1 
               
               
                   
               
               
                 515 
                 pNOP552746 
                 PIK3R1 
                 QINQNISSRWEIWLL 
                 &lt;0.1 
               
               
                   
               
               
                 516 
                 pNOP562357 
                 PIK3R1 
                 YTLRGLGNDRCARFG 
                 &lt;0.1 
               
               
                   
               
               
                 517 
                 pNOP576960 
                 PIK3R1 
                 NFQPYAFQILSSQL 
                 &lt;0.1 
               
               
                   
               
               
                 518 
                 pNOP577199 
                 PIK3R1 
                 NISSSSLKPPAKIC 
                 &lt;0.1 
               
               
                   
               
               
                 519 
                 pNOP594364 
                 PIK3R1 
                 EDMECWKQQPKQS 
                 &lt;0.1 
               
               
                   
               
               
                 520 
                 pNOP598433 
                 PIK3R1 
                 HCPASSYQARGSH 
                 &lt;0.1 
               
               
                   
               
               
                 521 
                 pNOP604234 
                 PIK3R1 
                 LQKYKAPKNIFSY 
                 &lt;0.1 
               
               
                   
               
               
                 522 
                 pNOP612549 
                 PIK3R1 
                 RSRQLSIEKLTNV 
                 &lt;0.1 
               
               
                   
               
               
                 523 
                 pNOP617271 
                 PIK3R1 
                 TTKTYYCSQQRYE 
                 &lt;0.1 
               
               
                   
               
               
                 524 
                 pNOP623223 
                 PIK3R1 
                 CTILFGIWKTWI 
                 &lt;0.1 
               
               
                   
               
               
                 525 
                 pNOP632080 
                 PIK3R1 
                 KKIGRRLEEAGS 
                 &lt;0.1 
               
               
                   
               
               
                 526 
                 pNOP632598 
                 PIK3R1 
                 KPHKSYRNFNLN 
                 &lt;0.1 
               
               
                   
               
               
                 527 
                 pNOP636330 
                 PIK3R1 
                 MVLGRYLEGRSE 
                 &lt;0.1 
               
               
                   
               
               
                 528 
                 pNOP664143 
                 PIK3R1 
                 KGQLLKHLMKP 
                 &lt;0.1 
               
               
                   
               
               
                 529 
                 pNOP703583 
                 PIK3R1 
                 LYSYTKERGK 
                 &lt;0.1 
               
               
                   
               
               
                 530 
                 pNOP402895 
                 PTEN 
                 QKMILTKQIKTKPTDTFLQILR 
                 3.02 
               
               
                   
               
               
                 531 
                 pNOP173513 
                 PTEN 
                 YQSRVLPQTEQDAKKGQNVSLLGKYILHTRTRGNLRKSRKWKSM 
                 2.64 
               
               
                   
               
               
                 532 
                 pNOP175050 
                 PTEN 
                 GFWIQSIKTITRYTIFVLKDIMTPPNLIAELHNILLKTITHHS 
                 1.51 
               
               
                   
               
               
                 533 
                 pNOP127569 
                 PTEN 
                 SWKGTNWCNDMCIFITSGQIFKGTRGPRFLWGSKDQRQKGSNYSQSEALCVLL 
                 0.94 
               
               
                   
               
               
                 534 
                 pNOP268063 
                 PTEN 
                 RYIPPIQDPHDGKTSSCTLSSLSRYLCVVISK 
                 0.94 
               
               
                   
               
               
                 535 
                 pNOP421008 
                 PTEN 
                 QPSSKRSLAETKGDIKRMDST 
                 0.94 
               
               
                   
               
               
                 536 
                 pNOP197013 
                 PTEN 
                 NYSNVQWRNLQSSVCGLPAKGEDIFLQFRTHTTGRQVHVL 
                 0.57 
               
               
                   
               
               
                 537 
                 pNOP325196 
                 PTEN 
                 PIFIQTLLLWDFLQKDLKAYTGTILMM 
                 0.57 
               
               
                   
               
               
                 538 
                 pNOP410561 
                 PTEN 
                 CLKLFQCSVAELAILSLWSAS 
                 0.57 
               
               
                   
               
               
                 539 
                 pNOP546300 
                 PTEN 
                 KMEVYVIKKSIAFAV 
                 0.57 
               
               
                   
               
               
                 540 
                 pNOP547556 
                 PTEN 
                 LFPVRGAMCIIIATC 
                 0.57 
               
               
                   
               
               
                 541 
                 pNOP143081 
                 PTEN 
                 HQMLVTMNLIIIDILTPLTLIQRMNLLMKISIHKLQKSEFFFIKRDKTP 
                 0.38 
               
               
                   
               
               
                 542 
                 pNOP266820 
                 PTEN 
                 QKQKEISRGWIRLRLDLYLSKHYCYGISCRKT 
                 0.19 
               
               
                   
               
               
                 543 
                 pNOP571289 
                 PTEN 
                 IHSSYQDQRKPQKK 
                 0.19 
               
               
                   
               
               
                 544 
                 pNOP606239 
                 PTEN 
                 NLSNPFVKILTNG 
                 0.19 
               
               
                   
               
               
                 545 
                 pNOP699983 
                 PTEN 
                 KPLQDIQSLC 
                 0.19 
               
               
                   
               
               
                 546 
                 pNOP102380 
                 PTEN 
                 WSGGEKRRRRRPRRLQLQGGGLSRLSPFPGLGTPESWSLPFYCLQHGGGGGGTSRDPGRF 
                 &lt;0.1 
               
               
                   
                   
                   
                 TSRPPPPHPPWPGLRRPPAEAAVRRIIRLLPIPLPPLPGLWLLRRSRPSRCNHPAAAAAAITRLRSRA 
                   
               
               
                   
                   
                   
                 KRR 
                   
               
               
                   
               
               
                 547 
                 pNOP25104 
                 PTEN 
                 QSEGHQLPPSPEPFPSCRRSPATSSFCHLSPPFSSATGSQT 
                 &lt;0.1 
               
               
                   
               
               
                 548 
                 pNOP341110 
                 PTEN 
                 RSAYTNYKSLNFFLSRGIKHHENKLE 
                 &lt;0.1 
               
               
                   
               
               
                 549 
                 pNOP401700 
                 PTEN 
                 PGAGGRSGGGGGRGGCSSREGV 
                 &lt;0.1 
               
               
                   
               
               
                 550 
                 pNOP445691 
                 PTEN 
                 VKMTIMLQQFTVKLERDELV 
                 &lt;0.1 
               
               
                   
               
               
                 551 
                 pNOP494212 
                 PTEN 
                 GEAVLHKNSRGAVKSRG 
                 &lt;0.1 
               
               
                   
               
               
                 552 
                 pNOP554260 
                 PTEN 
                 RIIWIIDQWHCCFTR 
                 &lt;0.1 
               
               
                   
                   
                   
                 VACHHFQGWERRRVGLSPSTASNTAAAAAAHPGTRAGFKPPVRRRRTPRGPGSGGRRRRQPFGGLF 
                   
               
               
                   
               
               
                 553 
                 pNOP55619 
                 PTEN 
                 VFSPFRCRRCQASGC 
                 &lt;0.1 
               
               
                   
                   
                   
                 GEAGPVAATIQQPPQQPLPGCGPEPSGGRARGISYRQVQSHFHPAEEAPPPAASAISLLLFLQPQA 
                   
               
               
                   
                   
                   
                 PRH 
                   
               
               
                   
               
               
                 554 
                 pNOP61010 
                 PTEN 
                 DSHHQRDR 
                 &lt;0.1 
               
               
                   
               
               
                 555 
                 pNOP612548 
                 PTEN 
                 RSRQIQRLAVQLL 
                 &lt;0.1 
               
               
                   
               
               
                 556 
                 pNOP672549 
                 PTEN 
                 PTTARTYQTLL 
                 &lt;0.1 
               
               
                   
               
               
                 557 
                 pNOP673116 
                 PTEN 
                 QGISSTYFNKK 
                 &lt;0.1 
               
               
                   
               
               
                 558 
                 pNOP676378 
                 PTEN 
                 RQSQPILFSKF 
                 &lt;0.1 
               
               
                   
               
               
                 559 
                 pNOP682176 
                 PTEN 
                 TSGTVVSQDDV 
                 &lt;0.1 
               
               
                   
               
               
                 560 
                 pNOP685797 
                 PTEN 
                 YVHIYYIGANF 
                 &lt;0.1 
               
               
                   
               
               
                 ARID1A: Sequences 1-101; more preferably sequences 1-35. 
               
               
                 KMT2B: Sequences 102-217, more preferably sequences 102-121. 
               
               
                 KMT2D: Sequences 218-472, more preferably sequences 218-242. 
               
               
                 PIK3R1: Sequences 473-529, more preferably sequences 473-487. 
               
               
                 PTEN: Sequences 530-560, more preferably sequences 530-545. 
               
            
           
         
       
     
     The most preferred neoantigens are ARID1A frameshift mutation peptides, followed by PTEN frameshift mutation peptides, followed by KMT2D frameshift mutation peptides, followed by KMT2B frameshift mutation peptides, followed by PIK3R1 frameshift mutation peptides. The preference for individual neoantigens directly correlates with the frequency of their occurrence in uterine cancer patients, with ARID1A frameshift mutation peptides covering at least 15% of uterine cancer patients, PTEN frameshift mutation peptides covering at least 8% of uterine cancer patients, KMT2D frameshift mutation peptides covering least 4.2% of uterine cancer patients, KMT2B frameshift mutation peptides covering at least 2.1% of uterine cancer patients, and PIK3R1 frameshift mutation peptides covering at least 2.1% of uterine cancer patients. 
     In a preferred embodiment the disclosure provides one or more frameshift-mutation peptides (also referred to herein as ‘neoantigens’) comprising an amino acid sequence selected from the groups: 
     (i) Sequences 530-560, an amino acid sequence having 90% identity to Sequences 530-560, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 530-560 
     (ii)Sequences 1-101, an amino acid sequence having 90% identity to Sequences 1-101, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 1-101; 
     (iii) Sequences 102-217, an amino acid sequence having 90% identity to Sequences 102-217, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 102-217; 
     (iv) Sequences 218-472, an amino acid sequence having 90% identity to Sequences 218-472, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 218-472; and 
     (v) Sequences 473-529, an amino acid sequence having 90% identity to Sequences 473-529, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 473-529. 
     As will be clear to a skilled person, the preferred amino acid sequences may also be provided as a collection of tiled sequences, wherein such a collection comprises two or more peptides that have an overlapping sequence. Such ‘tiled’ peptides have the advantage that several peptides can be easily synthetically produced, while still covering a large portion of the NOP. In an exemplary embodiment, a collection comprising at least 3, 4, 5, 6, 10, or more tiled peptides each having between 10-50, preferably 12-45, more preferably 15-35 amino acids, is provided. As described further herein, such tiled peptides are preferably directed to the C-terminus of a pNOP. As will be clear to a skilled person, a collection of tiled peptides comprising an amino acid sequence of Sequence X, indicates that when aligning the tiled peptides and removing the overlapping sequences, the resulting tiled peptides provide the amino acid sequence of Sequence X, albeit present on separate peptides. As is also clear to a skilled person, a collection of tiled peptides comprising a fragment of 10 consecutive amino acids of Sequence X, indicates that when aligning the tiled peptides and removing the overlapping sequences, the resulting tiled peptides provide the amino acid sequence of the fragment, albeit present on separate peptides. When providing tiled peptides, the fragment preferably comprises at least 20 consecutive amino acids of a sequence as disclosed herein. 
     Specific NOP sequences cover a large percentage of uterine cancer patients. Preferred NOP sequences, or subsequences of NOP sequence, are those that target the largest percentage of uterine cancer patients. Preferred sequences are, preferably in this order of preference, Sequence 530 (3% of uterine cancer patients), Sequence 531 (2.6% of uterine cancer patients), Sequence 1-3 (each covering 2.3% of uterine cancer patients), Sequence 4, 218, 473 (each covering 2.1% of uterine cancer patients), Sequence 5, 219 (each covering 1.9% of uterine cancer patients), Sequence 102 (1.7% of uterine cancer patients), Sequence 220, 532 (1.5% of uterine cancer patients), Sequence 6 (1.3% of uterine cancer patients), Sequence 7, 8, 9, 474 (each covering 1.1% of uterine cancer patients), Sequence 10, 103, 533-535 (each covering 0.9% of uterine cancer patients), Sequence 104, 221-222 (each covering 0.8% of uterine cancer patients), Sequence 11, 105-108, 536-540 (each covering 0.6% of uterine cancer patients), Sequence 12-23, 109-110, 475-477, 541 (each covering 0.4% of uterine cancer patients), Sequence 24-35, 111-121, 225-242,478-487, 542-545 (each covering 0.2% of uterine cancer patients), as well as Sequence 36-101, 122-217, 243-472,488-529, 546-560 (each covering less than 0.1% of uterine cancer patients). 
     As discussed further herein, neoantigens also include the nucleic acid molecules (such as DNA and RNA) encoding said amino acid sequences. The preferred sequences listed above are also the preferred sequences for the embodiments described further herein. 
     Preferably, the neoantigens and vaccines disclosed herein induce an immune response, or rather the neoantigens are immunogenic. Preferably, the neoantigens bind to an antibody or a T-cell receptor. In preferred embodiments, the neoantigens comprise an MHCI or MHCII ligand. 
     The major histocompatibility complex (MHC) is a set of cell surface molecules encoded by a large gene family in vertebrates. In humans, MHC is also referred to as human leukocyte antigen (HLA). An MHC molecule displays an antigen and presents it to the immune system of the vertebrate. Antigens (also referred to herein as ‘MHC ligands’) bind MHC molecules via a binding motif specific for the MHC molecule. Such binding motifs have been characterized and can be identified in proteins. See for a review Meydan et al. 2013 BMC Bioinformatics 14:S13. 
     MHC-class I molecules typically present the antigen to CD8 positive T-cells whereas MHC-class II molecules present the antigen to CD4 positive T-cells. The terms “cellular immune response” and “cellular response” or similar terms refer to an immune response directed to cells characterized by presentation of an antigen with class I or class II MHC involving T cells or T-lymphocytes which act as either “helpers” or “killers”. The helper T cells (also termed CD4+ T cells) play a central role by regulating the immune response and the killer cells (also termed cytotoxic T cells, cytolytic T cells, CD8+ T cells or CTLs) kill diseased cells such as cancer cells, preventing the production of more diseased cells. 
     In preferred embodiments, the present disclosure involves the stimulation of an anti-tumor CTL response against tumor cells expressing one or more tumor-expressed antigens (i.e., NOPs) and preferably presenting such tumor-expressed antigens with class I MHC. 
     In some embodiments, an entire NOP (e.g., Sequence 1) may be provided as the neoantigen (i.e., peptide). The length of the NOPs identified herein vary from around 10 to around 494 amino acids. Preferred NOPs are at least 20 amino acids in length, more preferably at least 30 amino acids, and most preferably at least 50 amino acids in length. While not wishing to be bound by theory, it is believed that neoantigens longer than 10 amino acids can be processed into shorter peptides, e.g., by antigen presenting cells, which then bind to MHC molecules. 
     In some embodiments, fragments of a NOP can also be presented as the neoantigen. The fragments comprise at least 8 consecutive amino acids of the NOP, preferably at least 10 consecutive amino acids, and more preferably at least 20 consecutive amino acids, and most preferably at least 30 amino acids. In some embodiments, the fragments can be about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 60, about 70, about 80, about 90, about 100, about 110, or about 120 amino acids or greater. Preferably, the fragment is between 8-50, between 8-30, or between 10-20 amino acids. As will be understood by the skilled person, fragments greater than about 10 amino acids can be processed to shorter peptides, e.g., by antigen presenting cells. 
     The specific mutations resulting in the generation of a neo open reading frame may differ between individuals resulting in differing NOP lengths. However, as depicted in, e.g.,  FIG. 2 , such individuals share common NOP sequences, in particular at the C-terminus of an NOP. While suitable fragments for use as neoantigens may be located at any position along the length of an NOP, fragments located near the C-terminus are preferred as they are expected to benefit a larger number of patients. Preferably, fragments of a NOP correspond to the C-terminal (3′) portion of the NOP, preferably the C-terminal 10 consecutive amino acids, more preferably the C-terminal 20 consecutive amino acids, more preferably the C-terminal 30 consecutive amino acids, more preferably the C-terminal 40 consecutive amino acids, more preferably the C-terminal 50 consecutive amino acids, more preferably the C-terminal 60 consecutive amino acids, more preferably the C-terminal 70 consecutive amino acids, more preferably the C-terminal 80 consecutive amino acids, more preferably the C-terminal 90 consecutive amino acids, and most preferably the C-terminal 100 or more consecutive amino acids. In some embodiments a subsequence of the preferred C-terminal portion of the NOP may be highly preferred for reasons of manufacturability, solubility and MHC binding strength. 
     Suitable fragments for use as neoantigens can be readily determined. The NOPs disclosed herein may be analysed by known means in the art in order to identify potential MHC binding peptides (i.e., MHC ligands). Suitable methods are described herein in the examples and include in silico prediction methods (e.g., ANNPRED, BIMAS, EPIMHC, HLABIND, IEDB, KISS, MULTIPRED, NetMHC, PEPVAC, POPI, PREDEP, RANKPEP, SVMHC, SVRMHC, and SYFFPEITHI, see Lundegaard 2010 130:309-318 for a review). MHC binding predictions depend on HLA genotypes, furthermore it is well known in the art that different MHC binding prediction programs predict different MHC affinities for a given epitope. While not wishing to be limited by such predictions, at least 60% of NOP sequences as defined herein, contain one or more predicted high affinity MHC class I binding epitope of 10 amino acids, based on allele HLA-A0201 and using NetMHC4.0. 
     A skilled person will appreciate that natural variations may occur in the genome resulting in variations in the sequence of an NOP. Accordingly, a neoantigen of the disclosure may comprise minor sequence variations, including, e.g., conservative amino acid substitutions. Conservative substitutions are well known in the art and refer to the substitution of one or more amino acids by similar amino acids. For example, a conservative substitution can be the substitution of an amino acid for another amino acid within the same general class (e.g., an acidic amino acid, a basic amino acid, or a neutral amino acid). A skilled person can readily determine whether such variants retain their immunogenicity, e.g., by determining their ability to bind MHC molecules. 
     Preferably, a neoantigen has at least 90% sequence identity to the NOPs disclosed herein. Preferably, the neoantigen has at least 95% or 98% sequence identity. The term “% sequence identity” is defined herein as the percentage of nucleotides in a nucleic acid sequence, or amino acids in an amino acid sequence, that are identical with the nucleotides, resp amino acids, in a nucleic acid or amino acid sequence of interest, after aligning the sequences and optionally introducing gaps, if necessary, to achieve the maximum percent sequence identity. The skilled person understands that consecutive amino acid residues in one amino acid sequence are compared to consecutive amino acid residues in another amino acid sequence. Methods and computer programs for alignments are well known in the art. Sequence identity is calculated over substantially the whole length, preferably the whole (full) length, of a sequence of interest. 
     The disclosure also provides at least two frameshift-mutation derived peptides (i.e., neoantigens), also referred to herein as a ‘collection’ of peptides. Preferably the collection comprises at least 3, at least 4, at least 5, at least 10, at least 15, or at least 20, or at least 50 neoantigens. In some embodiments, the collections comprise less than 20, preferably less than 15 neoantigens. Preferably, the collections comprise the top 20, more preferably the top 15 most frequently occurring neoantigens in cancer patients. The neoantigens are selected from: 
     (i) Sequences 530-560, an amino acid sequence having 90% identity to Sequences 530-560, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 530-560 
     (ii) Sequences 1-101, an amino acid sequence having 90% identity to Sequences 1-101, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 1-101; 
     (iii) Sequences 102-217, an amino acid sequence having 90% identity to Sequences 102-217, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 102-217; 
     (iv) Sequences 218-472, an amino acid sequence having 90% identity to Sequences 218-472, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 218-472; and 
     (v) Sequences 473-529, an amino acid sequence having 90% identity to Sequences 473-529, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 473-529. 
     Preferably, the collection comprises at least two frameshift-mutation derived peptides corresponding to the same gene. Preferably, a collection is provided comprising:
     (i) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 530, an amino acid sequence having 90% identity to Sequence 530, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 530; and   a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 531, an amino acid sequence having 90% identity to Sequence 531, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 531; preferably also comprising   a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 532, an amino acid sequence having 90% identity to Sequence 532, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 532;   (ii) at least two peptides, wherein each peptide, or a collection of tiled peptides, comprises a different amino acid sequence selected from Sequences 1-5, an amino acid sequence having 90% identity to Sequences 1-5, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 1-5;   (iii) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 102, an amino acid sequence having 90% identity to Sequence 102, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 102; and   a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 103, an amino acid sequence having 90% identity to Sequence 103, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 103;   (iv) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 218, an amino acid sequence having 90% identity to Sequence 218, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 218; and
       a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 219, an amino acid sequence having 90% identity to Sequence 219, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 219; preferably also comprising   a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 220, an amino acid sequence having 90% identity to Sequence 220, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 220; and/or   
       (v) a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 473, an amino acid sequence having 90% identity to Sequence 473, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 473; and   a peptide, or a collection of tiled peptides, having the amino acid sequence selected from Sequence 474, an amino acid sequence having 90% identity to Sequence 474, or a fragment thereof comprising at least 10 consecutive amino acids of Sequence 474.   

     In some embodiments, the collection comprises two or more neoantigens corresponding to the same NOP. For example, the collection may comprise two (or more) fragments of Sequence 1 or the collection may comprise a peptide having Sequence 1 and a peptide having 95% identity to Sequence 1. 
     Preferably, the collection comprises two or more neoantigens corresponding to different NOPs. In some embodiments, the collection comprises two or more neoantigens corresponding to different NOPs of the same gene. For example the peptide may comprise the amino acid sequence of Sequence 1 (or a fragment or collection of tiled fragments thereof) and the amino acid sequence of Sequence 2 (or a fragment or collection of tiled fragments thereof). 
     Preferably, the collection comprises Sequences 1-5, more preferably 1-10, even more preferably 1-23, most preferably 1-35 (or a fragment or collection of tiled fragments thereof). 
     Preferably, the collection comprises Sequences 102-104, more preferably 102-110, even more preferably 102-121, (or a fragment or collection of tiled fragments thereof). 
     Preferably, the collection comprises Sequences 218-220, more preferably 218-224, even more preferably 218-242, most preferably 1-35 (or a fragment or collection of tiled fragments thereof). 
     Preferably, the collection comprises Sequences 473-477, more preferably 473-487, (or a fragment or collection of tiled fragments thereof). 
     Preferably, the collection comprises Sequences 530-535, more preferably 530-540, even more preferably 530-545, (or a fragment or collection of tiled fragments thereof). 
     In some embodiments, the collection comprises two or more neoantigens corresponding to different NOPs of different genes. For example the collection may comprise a peptide having the amino acid sequence of Sequence 1 (or a fragment or collection of tiled fragments thereof) and a peptide having the amino acid sequence of Sequence 102 (or a fragment or collection of tiled fragments thereof). Preferably, the collection comprises at least one neoantigen from group (i) and at least one neoantigen from group (ii); at least one neoantigen from group (i) and at least one neoantigen from group (iii); at least one neoantigen from group (i) and at least one neoantigen from group (iv); at least one neoantigen from group (i) and at least one neoantigen from group (v); at least one neoantigen from group (ii) and at least one neoantigen from group (iii); at least one neoantigen from group (ii) and at least one neoantigen from group (iv); at least one neoantigen from group (ii) and at least one neoantigen from group (v); at least one neoantigen from group (iii) and at least one neoantigen from group (iv); at least one neoantigen from group (iii) and at least one neoantigen from group (v); or at least one neoantigen from group (iv) and at least one neoantigen from group (v). Preferably, the collection comprises at least one neoantigen from group (i), at least one neoantigen from group (ii), and at least one neoantigen from group (iii). Preferably, the collection comprises at least one neoantigen from each of groups (i) to (iv). Preferably, the collection comprises at least one neoantigen from each of groups (i) to (v). 
     In a preferred embodiment, the collections disclosed herein include Sequence 530, Sequence 531, and one, two or all of Sequence 1-3 (or a variant or fragment or collection of tiled fragments thereof as disclosed herein). In some embodiments, the collection further includes one, two or all of Sequence 4, 218, 473 (or a variant or fragment or collection of tiled fragments thereof as disclosed herein). In some embodiments, the collection further includes one or both of Sequence 5, 219 (or a variant or fragment or collection of tiled fragments thereof as disclosed herein). In some embodiments, the collection further includes one, two, or all of Sequence 102, 220, 532, 6 (or a variant or fragment or collection of tiled fragments thereof as disclosed herein). In some embodiments, the collection further includes one or more, preferably all of Sequence 7, 8, 9, 474, 10, 103, 533-535, 104, 221-222, 11, 105-108, 536-540 (or a variant or fragment or collection of tiled fragments thereof as disclosed herein). In some embodiments, the collection further includes one or more, preferably all of Sequence 12-23, 109-110, 475-477, 541, 24-35, 111-121, 225-242,478-487, 542-545, as well as Sequence 36-101, 122-217, 243-472,488-529, 546-560 (or a variant or fragment or collection of tiled fragments thereof as disclosed herein). 
     Such collections comprising multiple neoantigens have the advantage that a single collection (e.g, when used as a vaccine) can benefit a larger group of patients having different frameshift mutations. This makes it feasible to construct and/or test the vaccine in advance and have the vaccine available for off-the-shelf use. This also greatly reduces the time from screening a tumor from a patient to administering a potential vaccine for said tumor to the patient, as it eliminates the time of production, testing and approval. In addition, a single collection consisting of multiple neoantigens corresponding to different genes will limit possible resistance mechanisms of the tumor, e.g. by losing one or more of the targeted neoantigens. 
     In some embodiments, the neoantigens (i.e., peptides) are directly linked. Preferably, the neoantigens are linked by peptide bonds, or rather, the neoantigens are present in a single polypeptide. Accordingly, the disclosure provides polypeptides comprising at least two peptides (i.e., neoantigens) as disclosed herein. In some embodiments, the polypeptide comprises 3, 4, 5, 6, 7, 8, 9, 10 or more peptides as disclosed herein neoantigens). Such polypeptides are also referred to herein as ‘polyNOPs’. A collection of peptides can have one or more peptides and one or more polypeptides comprising the respective neoantigens. 
     In an exemplary embodiment, a polypeptide of the disclosure may comprise 10 different neoantigens, each neoantigen having between 10-400 amino acids. Thus, the polypeptide of the disclosure may comprise between 100-4000 amino acids, or more. As is clear to a skilled person, the final length of the polypeptide is determined by the number of neoantigens selected and their respective lengths. A collection may comprise two or more polypeptides comprising the neoantigens which can be used to reduce the size of each of the polypeptides. 
     In some embodiments, the amino acid sequences of the neoantigens are located directly adjacent to each other in the polypeptide. For example, a nucleic acid molecule may be provided that encodes multiple neoantigens in the same reading frame. In some embodiments, a linker amino acid sequence may be present. Preferably a linker has a length of 1, 2, 3, 4 or 5, or more amino acids. The use of linker may be beneficial, for example for introducing, among others, signal peptides or cleavage sites. In some embodiments at least one, preferably all of the linker amino acid sequences have the amino acid sequence VDD. 
     As will be appreciated by the skilled person, the peptides and polypeptides disclosed herein may contain additional amino acids, for example at the N- or C-terminus. Such additional amino acids include, e.g., purification or affinity tags or hydrophilic amino acids in order to decrease the hydrophobicity of the peptide. In some embodiments, the neoantigens may comprise amino acids corresponding to the adjacent, wild-type amino acid sequences of the relevant gene, i.e., amino acid sequences located 5′ to the frame shift mutation that results in the neo open reading frame. Preferably, each neoantigen comprises no more than 20, more preferably no more than 10, and most preferably no more than 5 of such wild-type amino acid sequences. 
     In preferred embodiments, the peptides and polypeptides disclosed herein have a sequence depicted as follows: 
       A-B-C-(D-E) n , wherein         A, C, and E are independently 0-100 amino acids   B and D are amino acid sequences as disclosed herein and selected from sequences 1-560, or an amino acid sequence having 90% identity to Sequences 1-560, or a fragment thereof comprising at least 10 consecutive amino acids of Sequences 1-560,   n is an integer from 0 to 500.       
     Preferably, B and D are different amino acid sequences. Preferably, n is an integer from 0-200. Preferably A, C, and E are independently 0-50 amino acids, more preferably independently 0-20 amino acids. 
     The peptides and polypeptides disclosed herein can be produced by any method known to a skilled person. In some embodiments, the peptides and polypeptide are chemically synthesized. The peptides and polypeptide can also be produced using molecular genetic techniques, such as by inserting a nucleic acid into an expression vector, introducing the expression vector into a host cell, and expressing the peptide. Preferably, such peptides and polypeptide are isolated, or rather, substantially isolated from other polypeptides, cellular components, or impurities. The peptide and polypeptide can be isolated from other (poly)peptides as a result of solid phase protein synthesis, for example. Alternatively, the peptides and polypeptide can be substantially isolated from other proteins after cell lysis from recombinant production (e.g., using HPLC). 
     The disclosure further provides nucleic acid molecules encoding the peptides and polypeptides disclosed herein. Based on the genetic code, a skilled person can determine the nucleic acid sequences which encode the (poly)peptides disclosed herein. Based on the degeneracy of the genetic code, sixty-four codons may be used to encode twenty amino acids and translation termination signal. 
     In a preferred embodiment, the nucleic acid molecules are codon optimized. As is known to a skilled person, codon usage bias in different organisms can effect gene expression level. Various computational tools are available to the skilled person in order to optimize codon usage depending on which organism the desired nucleic acid will be expressed. Preferably, the nucleic acid molecules are optimized for expression in mammalian cells, preferably in human cells. Table 2 lists for each acid amino acid (and the stop codon) the most frequently used codon as encountered in the human exome. 
     
       
         
           
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 most frequently used codon for each amino acid and  
               
               
                 most frequently used stop codon. 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 A 
                 GCC 
               
               
                 C 
                 TGC 
               
               
                 D 
                 GAC 
               
               
                 E 
                 GAG 
               
               
                 F 
                 TTC 
               
               
                 G 
                 GGC 
               
               
                 H 
                 CAC 
               
               
                 I 
                 ATC 
               
               
                 K 
                 AAG 
               
               
                 L 
                 CTG 
               
               
                 M 
                 ATG 
               
               
                 N 
                 AAC 
               
               
                 P 
                 CCC 
               
               
                 Q 
                 CAG 
               
               
                 R 
                 CGG 
               
               
                 S 
                 AGC 
               
               
                 T 
                 ACC 
               
               
                 V 
                 GTG 
               
               
                 W 
                 TGG 
               
               
                 Y 
                 TAC 
               
               
                 Stop 
                 TGA 
               
               
                   
               
            
           
         
       
     
     In some embodiments, at least 50%, 60%, 70%, 80%, 90%, or 100% of the amino acids are encoded by a codon corresponding to a codon presented in Table 2. 
     In some embodiments, the nucleic acid molecule encodes for a linker amino acid sequence in the peptide. Preferably, the nucleic acid sequence encoding the linker comprises at least one codon triplet that codes for a stop codon when a frameshift occurs. Preferably, said codon triplet is chosen from the group consisting of: ATA, CTA, GTA, TTA, ATO, CTG, GTG, TTG, AAA, AAC, AAG, AAT, AGA, AGC, AGG, AGT, GAA, GAC, GAG, and GAT. These codons do not code for a stop codon, but could create a stop codon in case of a frame shift, such as when read in the +1, +2, +4, +, 5, etc. reading frame. For example, two amino acid encoding sequences are linked by a linker amino acid encoding sequence as follows (linker amino acid encoding sequence in bold): 
     
       
         
           
               
               
            
               
                   
                 CTATACAGGCGA ATG AGATTATG 
               
            
           
         
       
     
     Resulting in the following amino acid sequence (amino acid linker sequence in bold): LYRRMRL 
     In case of a +1 frame shift, the following sequence is encoded: 
     YTGE [stop] DY 
     This embodiment has the advantage that if a frame shift occurs in the nucleotide sequence encoding the peptide, the nucleic acid sequence encoding the linker will terminate translation, thereby preventing expression of (part of) the native protein sequence for the gene related to peptide sequence encoded by the nucleotide sequence. 
     In some preferred embodiments, the linker amino acid sequences are encoded by the nucleotide sequence GTAGATGAC. This linker has the advantage that it contains two out of frame stop codons (TAG and TGA), one in the +1 and one in the −1 reading frame. The amino acid sequence encoded by this nucleotide sequence is VDD. The added advantage of using a nucleotide sequence encoding for this linker amino acid sequence is that any frame shift will result in a stop codon. 
     The disclosure also provides binding molecules and a collection of binding molecules that bind the neoantigens disclosed herein and or a neoantigen/MHC complex. In some embodiments the binding molecule is an antibody, a T-cell receptor, or an antigen binding fragment thereof. In some embodiments the binding molecule is a chimeric antigen receptor comprising i) a T cell activation molecule; ii) a transmembrane region; and iii) an antigen recognition moiety; wherein said antigen recognition moieties bind the neoantigens disclosed herein and or a neoantigen/MHC complex. 
     The term “antibody” as used herein refers to an immunoglobulin molecule that is typically composed of two identical pairs of polypeptide chains, each pair of chains consisting of one “heavy” chain with one “light” chain. The human light chains are classified as kappa and lambda. The heavy chains comprise different classes namely: mu, delta, gamma, alpha or epsilon. These classes define the isotype of the antibody, such as IgM, IgD, IgG IgA and IgE, respectively. These classes are important for the function of the antibody and help to regulate the immune response. Both the heavy chain and the light chain comprise a variable domain and a constant region. Each heavy chain variable region (VH) and light chain variable region (VL) comprises complementary determining regions (CDR) interspersed by framework regions (FR). The variable region has in total four FRs and three CDRs. These are arranged from the amino- to the carboxyl-terminus as follows: FR1. CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the light and heavy chain together form the antibody binding site and define the specificity for the epitope. 
     The term “antibody” encompasses murine, humanized, deimmunized, human, and chimeric antibodies, and an antibody that is a multimeric form of antibodies, such as dimers, trimers, or higher-order multimers of monomeric antibodies. The term antibody also encompasses monospecific, bispecific or multi-specific antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity. 
     Preferably, an antibody or antigen binding fragment thereof as disclosed herein is a humanized antibody or antigen binding fragment thereof. The term “humanized antibody” refers to an antibody that contains some or all of the CDRs from a non-human animal antibody while the framework and constant regions of the antibody contain amino acid residues derived from human antibody sequences. Humanized antibodies are typically produced by grafting CDRs from a mouse antibody into human framework sequences followed by back substitution of certain human framework residues for the corresponding mouse residues from the source antibody. The term “deimmunized antibody” also refers to an antibody of non-human origin in which, typically in one or more variable regions, one or more epitopes have been removed, that have a high propensity of constituting a human T-cell and/or B-cell epitope, for purposes of reducing immunogenicity. The amino acid sequence of the epitope can be removed in full or in part. However, typically the amino acid sequence is altered by substituting one or more of the amino acids constituting the epitope for one or more other amino acids, thereby changing the amino acid sequence into a sequence that does not constitute a human T-cell and/or B-cell epitope. The amino acids are substituted by amino acids that are present at the corresponding position(s) in a corresponding human variable heavy or variable light chain as the case may be. 
     In some embodiments, an antibody or antigen binding fragment thereof as disclosed herein is a human antibody or antigen binding fragment thereof. The term “human antibody” refers to an antibody consisting of amino acid sequences of human immunoglobulin sequences only. Human antibodies may be prepared in a variety of ways known in the art. 
     As used herein, antigen-binding fragments include Fab, F(ab′), F(ab′)2, complementarity determining region (CDR) fragments, single-chain antibodies (scFv), bivalent single-chain antibodies, and other antigen recognizing immunoglobulin fragments. 
     In some embodiments, the antibody or antigen binding fragment thereof is an isolated antibody or antigen binding fragment thereof. The term “isolated” as used herein refer to material which is substantially or essentially free from components which normally accompany it in nature. 
     In some embodiments, the antibody or antigen binding fragment thereof is linked or attached to a non-antibody moiety. In preferred embodiments, the non-antibody moiety is a cytotoxic moiety such as auristatins, maytanasines, calicheasmicins, duocarymycins, a-amanitin, doxorubicin, and centanamycin. Other suitable cytotoxins and methods for preparing such antibody drug conjugates are known in the art; see, e.g., WO2013085925A1 and WO2016133927A1. 
     Antibodies which bind a particular epitope can be generated by methods known in the art. For example, polyclonal antibodies can be made by the conventional method of immunizing a mammal (e.g., rabbits, mice, rats, sheep, goats). Polyclonal antibodies are then contained in the sera of the immunized animals and can be isolated using standard procedures (e.g., affinity chromatography, immunoprecipitation, size exclusion chromatography, and ion exchange chromatography). Monoclonal antibodies can be made by the conventional method of immunization of a mammal, followed by isolation of plasma B cells producing the monoclonal antibodies of interest and fusion with a myeloma cell (see, e.g., Mishell, B. B., et al., Selected Methods In Cellular Immunology, (W. H. Freeman, ed.) San Francisco (1980)). Peptides corresponding to the neoantiens disclosed herein may be used for immunization in order to produce antibodies which recognize a particular epitope. Screening for recognition of the epitope can be performed using standard immunoassay methods including ELISA techniques, radioimmunoassays, immunofluorescence, immunohistochemistry, and Western blotting. See, Short Protocols in Molecular Biology, Chapter 11, Green Publishing Associates and John Wiley &amp; Sons, Edited by Ausubel, F. M et al., 1992. In vitro methods of antibody selection, such as antibody phage display, may also be used to generate antibodies recognizing the neoantigens disclosed herein (see, e.g., Schirrmann et al. Molecules 2011 16:412-426). 
     T-cell receptors (TCRs) are expressed on the surface of T-cells and consist of an a chain and a β chain. TCRs recognize antigens bound to MHC molecules expressed on the surface of antigen-presenting cells. The T-cell receptor (TCR) is a heterodimeric protein, in the majority of cases (95%) consisting of a variable alpha (α) and beta (β) chain, and is expressed on the plasma membrane of T-cells. The TCR is subdivided in three domains: an extracellular domain, a transmembrane domain and a short intracellular domain. The extracellular domain of both α and β chains have an immunoglobulin-like structure, containing a variable and a constant region. The variable region recognizes processed peptides, among which neoantigens, presented by major histocompatibility complex (MHC) molecules, and is highly variable. The intracellular domain of the TCR is very short, and needs to interact with CD3ζ to allow for signal propagation upon ligation of the extracellular domain. 
     With the focus of cancer treatment shifted towards more targeted therapies, among which immunotherapy, the potential of therapeutic application of tumor-directed T-cells is increasingly explored. One such application is adoptive T-cell therapy (ATCT) using genetically modified T-cells that carry chimeric antigen receptors (CARS) recognizing a particular epitope (Ref Gomes-Silva 2018). The extracellular domain of the CAR is commonly formed by the antigen-specific subunit of (scFv) of a monoclonal antibody that recognizes a tumor-antigen (Ref Abate-Daga 2016). This enables the CAR T-cell to recognize epitopes independent of MHC-molecules, thus widely applicable, as their functionality is not restricted to individuals expressing the specific MHC-molecule recognized by the TCR. Methods for engineering TCRs that bind a particular epitope are known to a skilled person. See, for example, US20100009863A1, which describes methods of modifying one or more structural loop regions. The intracellular domain of the CAR can be a TCR intracellular domain or a modified peptide to enable induction of a signaling cascade without the need for interaction with accessory proteins. This is accomplished by inclusion of the CD3-signalling domain, often in combination with one or more co-stimulatory domains, such as CD28 and 4-1BB, which further enhance CAR T-cell functioning and persistence (Ref Abate-Daga 2016). 
     The engineering of the extracellular domain towards an scFv limits CAR T-cell to the recognition of molecules that are expressed on the cell-surface. Peptides derived from proteins that are expressed intracellularly can be recognized upon their presentation on the plasma membrane by MHC molecules, of which human form is called human leukocyte antigen (HLA). The HLA-haplotype generally differs among individuals, but some HLA types, like HLA-A*02:01, are globally common. Engineering of CAR T-cell extracellular domains recognizing tumor-derived peptides or neoantigens presented by a commonly shared HLA molecule enables recognition of tumor antigens that remain intracellular. Indeed CART-cells expressing a CAR with a TCR-like extracellular domain have been shown to be able to recognize tumor-derived antigens in the context of HLA-A*02:01 (Refs Zhang 2014, Ma 2016, Liu 2017). 
     In some embodiments, the binding molecules are monospecific, or rather they bind one of the neoantigens disclosed herein. In some embodiments, the binding molecules are bispecific, e.g., bispecific antibodies and bispecific chimeric antigen receptors. 
     In some embodiments, the disclosure provides a first antigen binding domain that binds a first neoantigen described herein and a second antigen binding domain that binds a second neoantigen described herein. The first and second antigen binding domains may be part of a single molecule, e.g., as a bispecific antibody or bispecific chimeric antigen receptor or they may be provided on separate molecules, e.g., as a collection of antibodies, T-cell receptors, or chimeric antigen receptors. In some embodiments, 3, 4, 5 or more antigen binding domains are provided each binding a different neoantigen disclosed herein. As used herein, an antigen binding domain includes the variable (antigen binding) domain of a T-cell receptor and the variable domain of an antibody (e.g., comprising a light chain variable region and a heavy chain variable region). 
     The disclosure further provides nucleic acid molecules encoding the antibodies, TCRs, and CARs disclosed herein. In a preferred embodiment, the nucleic acid molecules are codon optimized as disclosed herein. 
     The disclosure further provides vectors comprising the nucleic acids molecules disclosed herein. A “vector” is a recombinant nucleic acid construct, such as plasmid, phase genome, virus genome, cosmid, or artificial chromosome, to which another nucleic acid segment may be attached. The term “vector” includes both viral and non-viral means for introducing the nucleic acid into a cell in vitro, ex vivo or in vivo. The disclosure contemplates both DNA and RNA vectors. The disclosure further includes self-replicating RNA with (virus-derived) replicons, including but not limited to mRNA molecules derived from mRNA molecules from alphavirus genomes, such as the Sindbis, Semliki Forest and Venezuelan equine encephalitis viruses. 
     Vectors, including plasmid vectors, eukaryotic viral vectors and expression vectors are known to the skilled person. Vectors may be used to express a recombinant gene construct in eukaryotic cells depending on the preference and judgment of the skilled practitioner (see, for example, Sambrook et al., Chapter 16). For example, many viral vectors are known in the art including, for example, retroviruses, adeno-associated viruses, and adenoviruses. Other viruses useful for introduction of a gene into a cell include, but a not limited to, arenavirus, herpes virus, mumps virus, poliovirus, Sindbis virus, and vaccinia virus, such as, canary pox virus. The methods for producing replication-deficient viral particles and for manipulating the viral genomes are well known. In some embodiments, the vaccine comprises an attenuated or inactivated viral vector comprising a nucleic acid disclosed herein. 
     Preferred vectors are expression vectors. It is within the purview of a skilled person to prepare suitable expression vectors for expressing the inhibitors disclosed hereon. An “expression vector” is generally a DNA element, often of circular structure, having the ability to replicate autonomously in a desired host cell, or to integrate into a host cell genome and also possessing certain well-known features which, for example, permit expression of a coding DNA inserted into the vector sequence at the proper site and in proper orientation. Such features can include, but are not limited to, one or more promoter sequences to direct transcription initiation of the coding DNA and other DNA elements such as enhancers, polyadenylation sites and the like, all as well known in the art. Suitable regulatory sequences including enhancers, promoters, translation initiation signals, and polyadenylation signals may be included. Additionally, depending on the host cell chosen and the vector employed, other sequences, such as an origin of replication, additional DNA restriction sites, enhancers, and sequences conferring inducibility of transcription may be incorporated into the expression vector. The expression vectors may also contain a selectable marker gene which facilitates the selection of host cells transformed or transfected. Examples of selectable marker genes are genes encoding a protein such as G418 and hygromycin which confer resistance to certain drugs, β-galactosidase, chloramphenicol acetyltransferase, and firefly luciferase. 
     The expression vector can also be an RNA element that contains the sequences required to initiate translation in the desired reading frame, and possibly additional elements that are known to stabilize or contribute to replicate the RNA molecules after administration. Therefore when used herein the term DNA when referring to an isolated nucleic acid encoding the peptide according to the invention should be interpreted as referring to DNA from which the peptide can be transcribed or RNA molecules from which the peptide can be translated. 
     Also provided for is a host cell comprising an nucleic acid molecule or a vector as disclosed herein. The nucleic acid molecule may be introduced into a cell (prokaryotic or eukaryotic) by standard methods. As used herein, the terms “transformation” and “transfection” are intended to refer to a variety of art recognized techniques to introduce a DNA into a host cell. Such methods include, for example, transfection, including, but not limited to, liposome-polybrene, DEAE dextran-mediated transfection, electroporation, calcium phosphate precipitation, microinjection, or velocity driven microprojectiles (“biolistics”). Such techniques are well known by one skilled in the art. See, Sambrook et al. (1989) Molecular Cloning: A Laboratory Manaual (2 ed. Cold Spring Harbor Lab Press, Plainview, N.Y.). Alternatively, one could use a system that delivers the DNA construct in a gene delivery vehicle. The gene delivery vehicle may be viral or chemical. Various viral gene delivery vehicles can be used with the present invention. In general, viral vectors are composed of viral particles derived from naturally occurring viruses. The naturally occurring virus has been genetically modified to be replication defective and does not generate additional infectious viruses, or it may be a virus that is known to be attenuated and does not have unacceptable side effects. 
     Preferably, the host cell is a mammalian cell, such as MRCS cells (human cell line derived from lung tissue), HuH7 cells (human liver cell line), CHO-cells (Chinese Hamster Ovary), COS-cells (derived from monkey kidney (African green monkey), Vero-cells (kidney epithelial cells extracted from African green monkey), Hela-cells (human cell line), BHK-cells (baby hamster kidney cells, HEK-cells (Human Embryonic Kidney), NSO-cells (Murine myeloma cell line), C127-cells (nontumorigenic mouse cell line), PerC6®-cells (human cell line, Crucell), and Madin-Darby Canine Kidney(MDCK) cells. In some embodiments, the disclosure comprises an in vitro cell culture of mammalian cells expressing the neoantigens disclosed herein. Such cultures are useful, for example, in the production of cell-based vaccines, such as viral vectors expressing the neoantigens disclosed herein. 
     In some embodiments the host cells express the antibodies, TCRs, or CARs as disclosed herein. As will be clear to a skilled person, individual polypeptide chains (e.g., immunoglobulin heavy and light chains) may be provided on the same or different nucleic acid molecules and expressed by the same or different vectors. For example, in some embodiments, a host cell is transfected with a nucleic acid encoding an a-TCR polypeptide chain and a nucleic acid encoding a β-polypeptide chain. 
     In preferred embodiments, the disclosure provides T-cells expressing a TCR or CAR as disclosed herein. T cells may be obtained from, e.g., peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, spleen tissue, and tumors. Preferably, the T-cells are obtained from the individual to be treated (autologous T-cells). T-cells may also be obtained from healthy donors (allogenic T-cells). Isolated T-cells are expanded in vitro using established methods, such as stimulation with cytokines (IL-2). Methods for obtaining and expanding T-cells for adoptive therapy are well known in the art and are also described, e.g., in EP2872533A1. 
     The disclosure also provides vaccines comprising one or more neoantigens as disclosed herein. In particular, the vaccine comprises one or more (poly)peptides, antibodies or antigen binding fragments thereof, TCRs, CARS, nucleic acid molecules, vectors, or cells (or cell cultures) as disclosed herein. 
     The vaccine may be prepared so that the selection, number and/or amount of neoantigens (e.g., peptides or nucleic acids encoding said peptides) present in the composition is patient-specific. Selection of one or more neoantigens may be based on sequencing information from the tumor of the patient. For any frame shift mutation found, a corresponding NOP is selected. Preferably, the vaccine comprises more than one neoantigen corresponding to the NOP selected. In case multiple frame shift mutations (multiple NOPs) are found, multiple neoantigens corresponding to each NOP may be selected for the vaccine. 
     The selection may also be dependent on the specific type of cancer, the status of the disease, earlier treatment regimens, the immune status of the patient, and, HLA-haplotype of the patient. Furthermore, the vaccine can contain individualized components, according to personal needs of the particular patient. 
     As is clear to a skilled person, if multiple neoantigens are used, they may be provided in a single vaccine composition or in several different vaccines to make up a vaccine collection. The disclosure thus provides vaccine collections comprising a collection of tiled peptides, collection of peptides as disclosed herein, as well as nucleic acid molecules, vectors, or host cells as disclosed herein. As is clear to a skilled person, such vaccine collections may be administered to an individual simultaneously or consecutively (e.g., on the same day) or they may be administered several days or weeks apart. 
     Various known methods may be used to administer the vaccines to an individual in need thereof. For instance, one or more neoantigens can be provided as a nucleic acid molecule directly, as “naked DNA”. Neoantigens can also be expressed by attenuated viral hosts, such as vaccinia or fowlpox. This approach involves the use of a virus as a vector to express nucleotide sequences that encode the neoantigen. Upon introduction into the individual, the recombinant virus expresses the neoantigen peptide, and thereby elicits a host CTL response. Vaccination using viral vectors is well-known to a skilled person and vaccinia vectors and methods useful in immunization protocols are described in, e.g., U.S. Pat. No. 4,722,848. Another vector is BCG (Bacille Calmette Guerin) as described in Stover et al. (Nature 351:456-460 (1991)). 
     Preferably, the vaccine comprises a pharmaceutically acceptable excipient and/or an adjuvant. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like. Suitable adjuvants are well-known in the art and include, aluminum (or a salt thereof, e.g., aluminium phosphate and aluminium hydroxide), monophosphoryl lipid A, squalene (e.g., MF59), and cytosine phosphoguanine (CpG), montanide, liposomes (e.g. CAF adjuvants, cationic adjuvant formulations and variations thereof), lipoprotein conjugates (e.g. Amplivant), Resiquimod, Iscomatrix, hiltonol, poly-ICLC (polyriboinosinic-polyribocytidylic acid-polylysine carboxymethylcellulose). A skilled person is able to determine the appropriate adjuvant, if necessary, and an immune-effective amount thereof. As used herein, an immune-effective amount of adjuvant refers to the amount needed to increase the vaccine&#39;s immunogenicity in order to achieve the desired effect. 
     The disclosure also provides the use of the neoantigens disclosed herein for the treatment of disease, in particular for the treatment of uterine cancer in an individual. In some embodiments, the uterine cancer is Uterine Corpus Endometrial Carcinoma (UCEC). It is within the purview of a skilled person to diagnose an individual with as having uterine cancer. 
     As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, or inhibiting the progress of a disease, or reversing, alleviating, delaying the onset of, or inhibiting one or more symptoms thereof. Treatment includes, e.g., slowing the growth of a tumor, reducing the size of a tumor, and/or slowing or preventing tumor metastasis. 
     The term ‘individual’ includes mammals, both humans and non-humans and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. Preferably, the human is a mammal. 
     As used herein, administration or administering in the context of treatment or therapy of a subject is preferably in a “therapeutically effective amount”, this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. 
     The optimum amount of each neoantigen to be included in the vaccine composition and the optimum dosing regimen can be determined by one skilled in the art without undue experimentation. The composition may be prepared for injection of the peptide, nucleic acid molecule encoding the peptide, or any other carrier comprising such (such as a virus or liposomes). For example, doses of between 1 and 500 mg 50 μg and 1.5 mg, preferably 125 μg to 500 μg, of peptide or DNA may be given and will depend from the respective peptide or DNA. Other methods of administration are known to the skilled person. Preferably, the vaccines may be administered parenterally, e.g., intravenously, subcutaneously, intradermally, intramuscularly, or otherwise. 
     In preferred embodiments, the vaccines disclosed herein may be provided as a neoadjuvant therapy, e.g., prior to the removal of tumors or prior to treatment, e.g., with radiation or chemotherapy. Neoadjuvant therapy is intended to reduce the size of the tumor before more radical treatment is used. For that reason being able to provide the vaccine off-the-shelf or in a short period of time is very important. 
     In preferred embodiments, the vaccines disclosed herein may be provided shortly after the surgical removal of tumors. This can be followed by boosting doses until at least symptoms are substantially abated and for a period thereafter. 
     Also disclosed herein, the vaccine is capable of initiating a specific T-cell response. It is within the purview of a skilled person to measure such T-cell responses either in vivo or in vitro, e.g. by analyzing IFN-γ production or tumor killing by T-cells. In therapeutic applications, vaccines are administered to a patient in an amount sufficient to elicit an effective CTL response to the tumor antigen and to cure or at least partially arrest symptoms and/or complications. 
     In preferred embodiments, the vaccines disclosed herein may be provided in combination with other therapeutic agents. The therapeutic agent is for example, a chemotherapeutic agent, radiation, or immunotherapy, including but not limited to checkpoint inhibitors, such as nivolumab, ipilimumab, pembrolizumab, or the like. Any suitable therapeutic treatment for a particular, cancer may be administered. 
     The term “chemotherapeutic agent” refers to a compound that inhibits or prevents the viability and/or function of cells, and/or causes destruction of cells (cell death), and/or exerts anti-tumor/anti-proliferative effects. The term also includes agents that cause a cytostatic effect only and not a mere cytotoxic effect. Examples of chemotherapeutic agents include, but are not limited to bleomycin, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, interferon alpha, irinotecan, lansoprazole, levamisole, methotrexate, metoclopramide, mitomycin, omeprazole, ondansetron, paclitaxel, pilocarpine, rituxitnab, tamoxifen, taxol, trastuzumab, vinblastine, and vinorelbine tartrate. 
     Preferably, the other therapeutic agent is an anti-immunosuppressive/immunostimulatory agent, such as anti-CTLA antibody or anti-PD-1 or anti-PD-L1. Blockade of CTLA-4 or PD-L1 by antibodies can enhance the immune response to cancerous cells. In particular, CTLA-4 blockade has been shown effective when following a vaccination protocol. 
     As is understood by a skilled person the vaccine and other therapeutic agents may be provided simultaneously, separately, or sequentially. In some embodiments, the vaccine may be provided several days or several weeks prior to or following treatment with one or more other therapeutic agents. The combination therapy may result in an additive or synergistic therapeutic effect. 
     As disclosed herein, the present disclosure provides vaccines which can be prepared as off-the-shelf vaccines. As used herein “off-the-shelf” means a vaccine as disclosed herein that is available and ready for administration to a patient. For example, when a certain frame shift mutation is identified in a patient, the term “off-the-shelf” would refer to a vaccine according to the disclosure that is ready for use in the treatment of the patient, meaning that, if the vaccine is peptide based, the corresponding polyNOP peptide may, for example already be expressed and for example stored with the required excipients and stored appropriately, for example at −20° C. or −80° C. Preferably the term “off-the-shelf” also means that the vaccine has been tested, for example for safety or toxicity. More preferably the term also means that the vaccine has also been approved for use in the treatment or prevention in a patient. Accordingly, the disclosure also provides a storage facility for storing the vaccines disclosed herein. Depending on the final formulation, the vaccines may be stored frozen or at room temperature, e.g., as dried preparations. Preferably, the storage facility stores at least 20 or at least 50 different vaccines, each recognizing a neoantigen disclosed herein. 
     The present disclosure also contemplates methods which include determining the presence of NOPs in a tumor sample. In one embodiment, a tumor of a patient can be screened for the presence of frame shift mutations and an NOP can be identified that results from such a frame shift mutation. Based on the NOP(s) identified in the tumor, a vaccine comprising the relevant NOP(s) can be provided to immunize the patient, so the immune system of the patient will target the tumor cells expressing the neoantigen. An exemplary workflow for providing a neoantigen as disclosed herein is as follows. When a patient is diagnosed with a cancer, a biopsy may be taken from the tumor or a sample set is taken of the tumor after resection. The genome, exome and/or transcriptome is sequenced by any method known to a skilled person. The outcome is compared, for example using a web interface or software, to the library of NOPs disclosed herein. A patient whose tumor expresses one of the NOPs disclosed herein is thus a candidate for a vaccine comprising the NOP (or a fragment thereof). 
     Accordingly, the disclosure provides a method for determining a therapeutic treatment for an individual afflicted with cancer, said method comprising determining the presence of a frame shift mutation which results in the expression of an NOP selected from sequences 1-560. Identification of the expression of an NOP indicates that said individual should be treated with a vaccine corresponding to the identified NOP. For example, if it is determined that tumor cells from an individual express Sequence 1, then a vaccine comprising Sequence 1 or a fragment thereof is indicated as a treatment for said individual. 
     Accordingly, the disclosure provides a method for determining a therapeutic treatment for an individual afflicted with cancer, said method comprising
     a. performing complete, targeted or partial genome, exome, ORFeome, or transcriptome sequencing of at least one tumor sample obtained from the individual to obtain a set of sequences of the subject-specific tumor genome, exome, ORFeome, or transcriptome;   b. comparing at least one sequence or portion thereof from the set of sequences with one or more sequences selected from:   (i) Sequences 530-560;   (ii) Sequences 1-101;   (iii) Sequences 102-217;   (iv) Sequences 218-472; and   (v) Sequences 473-529;   c. identifying a match between the at least one sequence or portion thereof from the set of sequences and a sequence from groups (i) to (v) when the sequences have a string in common representative of at least 8 amino acids to identify a neoantigen encoded by a frameshift mutation;   

     wherein a match indicates that said individual is to be treated with the vaccine as disclosed herein. 
     As used herein the term “sequence” can refer to a peptide sequence, DNA sequence or RNA sequence. The term “sequence” will be understood by the skilled person to mean either or any of these, and will be clear in the context provided. For example, when comparing sequences to identify a match, the comparison may be between DNA sequences, RNA sequences or peptide sequences, but also between DNA sequences and peptide sequences. In the latter case the skilled person is capable of first converting such DNA sequence or such peptide sequence into, respectively, a peptide sequence and a DNA sequence in order to make the comparison and to identify the match. As is clear to a skilled person, when sequences are obtained from the genome or exome, the DNA sequences are preferably converted to the predicted peptide sequences. In this way, neo open reading frame peptides are identified. 
     As used herein the term “exome” is a subset of the genome that codes for proteins. An exome can be the collective exons of a genome, or also refer to a subset of the exons in a genome, for example all exons of known cancer genes. 
     As used herein the term “transcriptome” is the set of all RNA molecules is a cell or population of cells. In a preferred embodiment the transcriptome refers to all mRNA. 
     In some preferred embodiments the genome is sequenced. In some preferred embodiments the exome is sequenced. In some preferred embodiments the transcriptome is sequenced. In some preferred embodiments a panel of genes is sequenced, for example ARID1A, PTEN, KMT2D, KMT2B, and PIK3R1. In some preferred embodiments a single gene is sequenced. Preferably the transcriptome is sequenced, in particular the mRNA present in a sample from a tumor of the patient. The transcriptome is representative of genes and neo open reading frame peptides as defined herein being expressed in the tumor in the patient. 
     As used herein the term “sample” can include a single cell or multiple cells or fragments of cells or an aliquot of body fluid, taken from an individual, by means including venipuncture, excretion, ejaculation, massage, biopsy, needle aspirate, lavage sample, scraping, surgical incision, or intervention or other means known in the art. The DNA and/or RNA for sequencing is preferably obtained by taking a sample from a tumor of the patient. The skilled person knowns how to obtain samples from a tumor of a patient and depending on the nature, for example location or size, of the tumor. Preferably the tumor is a uterine tumor. Preferably the sample is obtained from the patient by biopsy or resection. The sample is obtained in such manner that is allows for sequencing of the genetic material obtained therein. In order to prevent a less accurate identification of at least one antigen, preferably the sequence of the tumor sample obtained from the patient is compared to the sequence of other non-tumor tissue of the patient, usually blood, obtained by known techniques (e.g. venipuncture). 
     Identification of frame shift mutations can be done by sequencing of RNA or DNA using methods known to the skilled person. Sequencing of the genome, exome, ORFeome, or transcriptome may be complete, targeted or partial. In some embodiments the sequencing is complete (whole sequencing). In some embodiments the sequencing is targeted. With targeted sequencing is meant that purposively certain region or portion of the genome, exome, ORFeome or transcriptome are sequenced. For example targeted sequencing may be directed to only sequencing for sequences in the set of sequences obtained from the cancer patient that would provide for a match with one or more of the sequences in the sequence listing, for example by using specific primers. In some embodiment only portion of the genome, exome, ORFeome or transcriptome is sequenced. The skilled person is well-aware of methods that allow for whole, targeted or partial sequencing of the genome, exome, ORFeome or transcriptome of a tumor sample of a patient. For example any suitable sequencing-by-synthesis platform can be used including the Genome Sequencers from Illumina/Solexa, the Ion Torrent system from Applied BioSystems, and the RSII or Sequel systems from Pacific Biosciences. Alternatively Nanopore sequencing may be used, such as the MinION, GridION or PromethION platform offered by Oxford Nanopore Technologies. The method of sequencing the genome, exome, ORFeome or transcriptome is not in particular limited within the context of the present invention. 
     Sequence comparison can be performed by any suitable means available to the skilled person. Indeed the skilled person is well equipped with methods to perform such comparison, for example using software tools like BLAST and the like, or specific software to align short or long sequence reads, accurate or noisy sequence reads to a reference genome, e.g. the human reference genome GRCh37 or GRCh38. A match is identified when a sequence identified in the patients material and a sequence as disclosed herein have a string, i.e. a peptide sequence (or RNA or DNA sequence encoding such peptide (sequence) in case the comparison is on the level of RNA or DNA) in common representative of at least 8, preferably at least 10 adjacent amino acids. Furthermore, sequence reads derived from a patients cancer genome (or transcriptome) can partially match the genomic DNA sequences encoding the amino acid sequences as disclosed herein, for example if such sequence reads are derived from exon/intron boundaries or exon/exon junctions, or if part of the sequence aligns upstream (to the 5′ end of the gene) of the position of a frameshift mutation. Analysis of sequence reads and identification of frameshift mutations will occur through standard methods in the field. For sequence alignment, aligners specific for short or long reads can be used, e.g. BWA (Li and Durbin, Bioinformatics. 2009 Jul. 15; 25(14):1754-60) or Minimap2 (Li, Bioinformatics. 2018 Sep. 15; 34(18):3094-3100). Subsequently, frameshift mutations can be derived from the read alignments and their comparison to a reference genome sequence (e.g. the human reference genome GRCh37) using variant calling tools, for example Genome Analysis ToolKit (GATK), and the like (McKenna et al. Genome Res. 2010 September; 20(9):1297-303). 
     A match between an individual patient&#39;s tumor sample genome or transcriptome sequence and one or more NOPs disclosed herein indicates that said tumor expresses said NOP and that said patient would likely benefit from treatment with a vaccine comprising said NOP (or a fragment thereof). More specifically, a match occurs if a frameshift mutation is identified in said patient&#39;s tumor genome sequence and said frameshift leads to a novel reading frame (+1 or −1 with respect to the native reading from of a gene). In such instance, the predicted out-of-frame peptide derived from the frameshift mutation matches any of the sequences 1-560 as disclosed herein. In some embodiments, said patient is administered said NOP (e.g., by administering the peptides, nucleic acid molecules, vectors, host cells or vaccines as disclosed herein). 
     In some embodiments, the methods further comprise sequencing the genome, exome, ORFeome, or transcriptome (or a part thereof) from a normal, non-tumor sample from said individual and determining whether there is a match with one or more NOPs identified in the tumor sample. Although the neoantigens disclosed herein appear to be specific to tumors, such methods may be employed to confirm that the neoantigen is tumor specific and not, e.g., a germline mutation. 
     The disclosure further provides the use of the neoantigens and vaccines disclosed herein in prophylactic methods from preventing or delaying the onset of uterine cancer. Approximately 3% of women will develop uterine cancer and the neo open reading frames disclosed herein occur in up to 30% of the uterine endometrial cancer patients. Prophylactic vaccination based on frameshift resulting peptides disclosed herein would thus provide protection to approximately 0.09% of the general population of women. The vaccine may be specifically used in a prophylactic setting for individuals having an increased risk of developing cancer. For example, prophylactic vaccination is expected to provide possible protection to 30% of all individuals at risk for uterine cancer (e.g. as a result of a predisposing mutation) and who would develop cancer as a result of this risk factor (predisposing mutation). In some embodiments, the prophylactic methods are useful for individuals who are genetically related to individuals afflicted with uterine cancer. In some embodiments, the prophylactic methods are useful for individuals suffering from Lynch syndrome, in particular those having germline mutations in genes involved in mismatch repair, including MLH1, MSH2, MLH3, MSH6, and PMS1, PMS2, TGFBR2, or the EPCAM gene. In some embodiments, the prophylactic methods are useful for the general population. 
     In some embodiments, the individual is at risk of developing cancer. It is understood to a skilled person that being at risk of developing cancer indicates that the individual has a higher risk of developing cancer than the general population; or rather the individual has an increased risk over the average of developing cancer. Such risk factors are known to a skilled person and include being a woman; having an excess of endogenous or exogenous estrogen without adequate opposition by a progestin (eg, postmenopausal estrogen therapy without a progestin), tamoxifen, therapy, obesity, type 2 diabetes, having a family history of utereine cancer, suffering from Lynch syndrome (hereditary nonpolyposis colon cancer), and having a mutation in a gene that predisposes an individual to uterine cancer. 
     As used herein, “to comprise” and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. In addition, the verb “to consist” may be replaced by “to consist essentially of” meaning that a compound or adjunct compound as defined herein may comprise additional component(s) than the ones specifically identified, said additional component(s) not altering the unique characteristic of the invention. 
     The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. 
     The word “approximately” or “about” when used in association with a numerical value (approximately 10, about 10) preferably means that the value may be the given value of 10 more or less 1% of the value. 
     All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety. 
     For the purpose of clarity and a concise description features are described herein as part of the same or separate embodiments, however, it will be appreciated that the scope of the invention may include embodiments having combinations of all or some of the features described. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  Frame shift initiated translation in the TCGA (n=10,186) cohort is of sufficient size for immune presentation. A. Peptide length distribution of frame shift mutation initiated translation up to the first encountered stop codon. Dark shades are unique peptide sequences derived from frameshift mutations, light shade indicates the total sum (unique peptides derived from frameshifts multiplied by number of patients containing that frameshift). B. Gene distribution of peptides with length 10 or longer and encountered in up to 10 patients. 
         FIG. 2  Neo open reading frame peptides (TCGA cohort) concerge on common peptide sequences. Graphical representation in an isoform of TP53, where amino acids are colored distinctly. A. somatic single nucleotide variants, B. positions of frame shift mutations on the −1 and the +1 frame. C. amino acid sequence of TP53. D. Peptide (10aa) library (n=1,000) selection. Peptides belonging to −1 or +1 frame are separated vertically E,F pNOPs for the different frames followed by all encountered frame shift mutations (rows), translated to a stop codon (lines) colored by amino acid. 
         FIG. 3  A recurrent peptide selection procedure can generate a ‘fixed’ library to cover up to 50% of the TOGA cohort. Graph depicts the number of unique patients from the TCGA cohort (10,186 patients) accommodated by a growing library of 10-mer peptides, picked in descending order of the number patients with that sequence in their NOPs. A peptide is only added if it adds a new patient from the TCGA cohort. The dark blue line shows that an increasing number of 10-mer peptides covers an increasing number of patients from the TCGA cohort (up to 50% if using 3000 unique 10-mer peptides). Light shaded blue line depicts the number of patients containing the peptide that was included (right Y-axis). The best peptide covers 89 additional patients from the TCGA cohort (left side of the blue line), the worst peptide includes only 1 additional patient (right side of the blue line). 
         FIG. 4  For some cancers up to 70% of patients contain a recurrent NOP. TCGA cohort ratio of patients separated by tumor type that could be ‘helped’ using optimally selected peptides for genes encountered most often within a cancer. Coloring represents the ratio, using 1, 2 . . . 10 genes, or using all encountered genes (lightest shade) 
         FIG. 5  Examples of NOPs. Selection of genes containing NOPs of 10 or more amino acids. 
         FIG. 6  Frame shift presence in mRNA from 58 COLE colorectal cancer cell lines. 
       a. Cumulative counting of RNAseq allele frequency (Samtools mpileup (XO:1/all)) at the genomic position of DNA detected frame shift mutations. 
       b. IGV examples of frame shift mutations in the BAM files of CCLE cell lines. 
         FIG. 7  Example of normal isoforms, using shifted frame. 
       Genome model of CDKN2A with the different isoforms are shown on the minus strand of the genome. Zoom of the middle exon depicts the 2 reading frames that are encountered in the different isoforms. 
         FIG. 8  Gene prevalence is Cancer type. 
       Percentage of frameshift mutations (resulting in peptides of 10 aa or longer), assessed by the type of cancer in the TCGA cohort. Genes where 50% or more of the frameshifts occur within a single tumor type are indicated in bold. Cancer type abbreviations are as follows: 
       LAML Acute Myeloid Leukemia 
       ACC Adrenocortical carcinoma 
       BLCA Bladder Urothelial Carcinoma 
       LGG Brain Lower Grade Glioma 
       BRCA Breast invasive carcinoma 
       CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma 
       CHOL Cholangiocarcinoma 
       LCML Chronic Myelogenous Leukemia 
       COAD Colon adenocarcinoma 
       CNTL Controls 
       ESCA Esophageal carcinoma 
       GBM Glioblastoma multiforme 
       HNSC Head and Neck squamous cell carcinoma 
       KICH Kidney Chromophobe 
       KIRC Kidney renal clear cell carcinoma 
       KIRP Kidney renal papillary cell carcinoma 
       LIHC Liver hepatocellular carcinoma 
       LUAD Lung adenocarcinoma 
       LUSC Lung squamous cell carcinoma 
       DLBC Lymphoid Neoplasm Diffuse Large B-cell Lymphoma 
       MESO Mesothelioma 
       MISC Miscellaneous 
       OV Ovarian serous cystadenocarcinoma 
       PAAD Pancreatic adenocarcinoma 
       PCPG Pheochromocytoma and Paraganglioma 
       PRAD Prostate adenocarcinoma 
       READ Rectum adenocarcinoma 
       SARC Sarcoma 
       SKCM Skin Cutaneous Melanoma 
       STAD Stomach adenocarcinoma 
       TGCT Testicular Germ Cell Tumors 
       THYM Thymoma 
       THCA Thyroid carcinoma 
       UCS Uterine Carcinosarcoma 
       UCEC Uterine Corpus Endometrial Carcinoma 
       UVM Uveal Melanoma 
         FIG. 9  NOPs in the MSK-IMPACT study 
       Frame shift analysis in the targeted sequencing panel of the MSK-IMPACT study, covering up to 410 genes in more 10,129 patients (with at least 1 somatic mutation). a. FS peptide length distribution, b. Gene count of patients containing NC/Ps of 10 or more amino acids. c. Ratio of patients separated by tumor type that possess a neo epitope using optimally selected peptides for genes encountered most often within a cancer. Coloring represents the ratio, using 1, 2 . . . 10 genes, or using all encountered genes (lightest shade) d. Examples of NOPs for 4 genes. 
         FIGS. 10-14  Out-of-frame peptide sequences based on frameshift mutations in uterine cancer patients, for  FIG. 10  (ARID1A),  FIG. 11  (PIK3R1),  FIG. 12  (PTEN),  FIG. 13  (KMT2B), and  FIG. 14  (KMT2D). 
     
    
    
     EXAMPLES 
     We have analyzed 10,186 cancer genomes from 33 tumor types of the 40 TCGA (The Cancer Genome Atlas 22 ) and focused on the 143,444 frame shift mutations represented in this cohort. Translation of these mutations after re-annotation to a RefSeq annotation, starting in the protein reading frame, can lead to 70,439 unique peptides that are 10 or more amino acids in length (a cut off we have set at a size sufficient to shape a distinct epitope in the context of MHC ( FIG. 1 a   ). The list of genes most commonly represented in the cohort and containing such frame shift mutations is headed nearly exclusively by tumor driver genes, such as NF1, RB, BRCA2 ( FIG. 1 b   ) whose whole or partial loss of function apparently contributes to tumorigenesis. Note that a priori frame shift mutations are expected to result in loss of gene function more than a random SNV, and more independent of the precise position. NOPs initiated from a frameshift mutation and of a significant size are prevalent in tumors, and are enriched in cancer driver genes. Alignment of the translated NOP products onto the protein sequence reveals that a wide array of different frame shift mutations translate in a common downstream stretch of neo open reading frame peptides (‘NOPs’), as dictated by the −1 and +1 alternative reading frames. While we initially screened for NOPs of ten or more amino acids, their open reading frame in the out-of-frame genome often extends far beyond that search window. As a result we see ( FIG. 2 ) that hundreds of different frame shift mutations all at different sites in the gene nevertheless converge on only a handful of NOPs. Similar patterns are found in other common driver genes ( FIG. 5 ).  FIG. 2  illustrates that the precise location of a frame shift does not seem to matter much; the more or less straight slope of the series of mutations found in these 10,186 tumors indicates that it is not relevant for the biological effect (presumably reduction/loss of gene function) where the precise frame shift is, as long as translation stalls in the gene before the downstream remainder of the protein is expressed. As can also be seen in  FIG. 2 , all frame shift mutations alter the reading frame to one of the two alternative frames. Therefore, for potential immunogenicity the relevant information is the sequence of the alternative ORFs and more precisely, the encoded peptide sequence between 2 stop codons. We term these peptides ‘proto Neo Open Reading Frame peptides’ or pNOPs, and generated a full list of all thus defined out of frame protein encoding regions in the human genome, of 10 amino acids or longer. We refer to the total sum of all Neo-ORFs as the Neo-ORFeome. The Neo-ORFeome contains all the peptide potential that the human genome can generate after simple frame-shift induced mutations. The size of the Neo-ORFeome is 46.6 Mb. To investigate whether or not Nonsense Mediated Decay would wipe out frame shift mRNAs, we turned to a public repository containing read coverage for a large collection of cell lines (CCLE). We processed the data in a similar fashion as for the TCGA, identified the locations of frame shifts and subsequently found that, in line with the previous literature 23-25 , at least a large proportion of expressed genes also contained the frame shift mutation within the expressed mRNAs ( FIG. 6 ). On the mRNA level, NOPs can be detected in RNAseq data. We next investigated how the number of patients relates to the number of NOPs. We sorted 10-mer peptides from NOPs by the number of new patients that contain the queried peptide. Assessed per tumor type, frame shift mutations in genes with very low to absent mRNA expression were removed to avoid overestimation. Of note NOP sequences are sometimes also encountered in the normal ORFeome, presumably as result of naturally occuring isoforms (e,g,  FIG. 7 ). Also these peptides were excluded. We can create a library of possible ‘vaccines’ that is optimally geared towards covering the TCGA cohort, a cohort large enough that, also looking at the data presented here, it is representative of future patients ( FIG. 10 ). Using this strategy 30% of all patients can be covered with a fixed collection of only 1,244 peptides of length 10 ( FIG. 3 ). Since tumors will regularly have more than 1 frame shift mutation, one can use a ‘cocktail’ of different NOPs to optimally attack a tumor. Indeed, given a library of 1,244 peptides, 27% of the covered TCGA patients contain 2 or more ‘vaccine’ candidates. In conclusion, using a limited pool with optimal patient inclusion of vaccines, a large proportion of patients is covered. Strikingly, using only 6 genes (TP53, ARID1A, KMT2D, GATA3, APC, PTEN), already 10% of the complete TCGA cohort is covered. Separating this by the various tumor types, we find that for some cancers (like Pheochromocytoma and Paraganglioma (PCPG) or Thyroid carcinoma (THCA)) the hit rate is low, while for others up to 39% can be covered even with only 10 genes (Colon adenocarcinoma (COAD) using 60 peptides, Uterine Corpus Endometrial Carcinoma (UCEC) using 90 peptides),  FIG. 4 . At saturation (using all peptides encountered more than once) 50% of TCGA is covered and more than 70% can be achieved for specific cancer types (COAD, UCEC, Lung squamous cell carcinoma (LUSC) 72%, 73%, 73% respectively). As could be expected, these roughly follow the mutational load in the respective cancer types. In addition some frame shifted genes are highly enriched in specific tumor types (e.g. VHL, GATA3.  FIG. 8 ). We conclude that at saturating peptide coverage, using only very limited set of genes, a large cohort of patients can be provided with off the shelf vaccines. To validate the presence of NOPs, we used the targeted sequencing data on 10,129 patients from the MSK-IMPACT cohort 26. For the 341-410 genes assessed in this cohort, we obtained strikingly similar results in terms of genes frequently affected by frame shifts and the NOPs that they create ( FIG. 9 ). Even within this limited set of genes, 86% of the library peptides (in genes targeted by MSK-IMPACT) were encountered in the patient set. Since some cancers, like glioblastoma or pancreatic cancer, show survival expectancies after diagnosis measured in months rather than years (e.g. see 27), it is of importance to move as much of the work load and time line to the moment before diagnosis. Since the time of whole exome sequencing after biopsy is currently technically days, and since the scan of a resulting sequence against a public database describing these NOPs takes seconds, and the shipment of a peptide of choice days, a vaccination can be done theoretically within days and practically within a few weeks after biopsy. This makes it attractive to generate a stored and quality controlled peptide vaccine library based on the data presented here, possibly with replicates stored on several locations in the world. The synthesis in advance will—by economics of scale—reduce costs, allow for proper regulatory oversight, and can be quality certified, in addition to saving the patient time and thus provide chances. The present invention will likely not replace other therapies, but be an additional option in the treatment repertoire. The advantages of scale also apply to other means of vaccination against these common neoantigens, by RNA- or DNA-based approaches (e.g. 28), or recombinant bacteria (e.g. 29). The present invention also provides neoantigen directed application of the CAR-T therapy (For recent review see 30, and references therein), where the T-cells are directed not against a cell-type specific antigens (such as CD19 or CD20), but against a tumor specific neoantigen as provided herein. E.g. once one functional T-cell against any of the common p53 NOPs ( FIG. 2 ) is identified, the recognition domains can be engineered into T-cells for any future patient with such a NOP, and the constructs could similarly be deposited in an off-the-shelf library. In the present invention, we have identified that various frame shift mutations can result in a source for common neo open reading frame peptides, suitable as pre-synthesized vaccines. This may be combined with immune response stimulating measures such as but not limited checkpoint inhibition to help instruct our own immune system to defeat cancer. 
     Methods: 
     TCGA frameshift mutations—Frame shift mutations were retrieved from Varscan and mutect files per tumor type via https://portal.gdc.cancer.gov/. Frame shift mutations contained within these files were extracted using custom perl scripts and used for the further processing steps using HG38 as reference genome build. 
     CCLE frameshift mutations—For the CCLE cell line cohort, somatic mutations were retrieved from 
     http ://www.broadinstitute.org/ccle/data/browseDate?conversationPropagation=begin (CCLE_hybrid_capture1650_hg19_NoCommonSNPs_NoNeutralVariants_CDS_201 2.02.20.maf). Frame shift mutations were extracted using custom perl scripts using hg19 as reference genome. 
     Refseq annotation—To have full control over the sequences used within our analyses, we downloaded the reference sequences from the NCBI website (2018 Feb. 27) and extracted mRNA and coding sequences from the gbff files using custom perl scripts. Subsequently, mRNA and every exon defined within the mRNA sequences were aligned to the genome (hg19 and hg38) using the BLAT suite. The best mapping locations from the psl files were subsequently used to place every mRNA on the genome, using the separate exons to perform fine placement of the exonic borders. Using this procedure we also keep track of the offsets to enable placement of the amino acid sequences onto the genome. 
     Mapping genome coordinate onto Refseq—To assess the effect of every mentioned frame shift mutation within the cohorts (CCLE or TCGA), we used the genome coordinates of the frameshifts to obtain the exact protein position on our reference sequence database, which were aligned to the genome builds. This step was performed using custom perl scripts taking into account the codon offsets and strand orientation, necessary for the translation step described below. 
     Translation of FS peptides—Using the reference sequence annotation and the positions on the genome where a frame shift mutation was identified, the frame shift mutations were used to translate peptides until a stop codon was encountered. The NOP sequences were recorded and used in downstream analyses as described in the text. 
     Verification of FS mRNA expression in the CCLE colorectal cancer cell lines—For a set of 59 colorectal cancer cell lines, the HG19 mapped bam files were downloaded from https://portal.gdc.cancer.gov/. Furthermore, the locations of FS mutations were retrieved from 
     CCLE_hybrid_capture1650_hg19_NoCommonSNPs_NoNeutralVariants_CDS_201 2.02.20.maf 
     (http://www.broadinstitute.org/ccle/data/browseData?conversationPropagation=beg in), by selection only frameshift entries. Entries were processed similarly to to the TCGA data, but this time based on a HG19 reference genome. To get a rough indication that a particular location in the genome indeed contains an indel in the RNAseq data, we first extracted the count at the location of a frameshift by making use of the pileup function in samtools. Next we used the special tag XO:1 to isolate reads that contain an indel in it. On those bam files we again used the pileup function to count the number of reads containing an indel (assuming that the indel would primarily be found at the frameshift instructed location). Comparison of those 2 values can then be interpreted as a percentage of indel at that particular location. To reduce spurious results, at least 10 reads needed to be detected at the FS location in the original bam file. 
     Defining peptide library—To define peptide libraries that are maximized on performance (covering as many patients with the least amount of peptides) we followed the following procedure. From the complete TCGA cohort, FS translated peptides of size 10 or more (up to the encountering of a stop codon) were cut to produce any possible 10-mer. Then in descending order of patients containing a 10-mer, a library was constructed. A new peptide was added only if an additional patient in the cohort was included. peptides were only considered if they were seen 2 or more times in the TCGA cohort, if they were not filtered for low expression (see Filtering for low expression section), and if the peptide was not encountered in the orfeome (see Filtering for peptide presence orfeome). In addition, since we expect frame shift mutations to occur randomly and be composed of a large array of events (insertions and deletions of any non triplet combination), frame shift mutations being encountered in more than 10 patients were omitted to avoid focusing on potential artefacts. Manual inspection indicated that these were cases with e.g. long stretches of Cs, where sequencing errors are common. 
     Filtering for low expression—Frameshift mutations within genes that are not expressed are not likely to result in the expression of a peptide. To take this into account we calculated the average expression of all genes per TCGA entity and arbitrarily defined a cutoff of 2 log2 units as a minimal expression. Any frameshift mutation where the average expression within that particular entity was below the cutoff was excluded from the library. This strategy was followed, since mRNA gene expression data was not available for every TCGA sample that was represented in the sequencing data set. Expression data (RNASEQ v2) was pooled and downloaded from the R2 platform (http://r2.amc.nl). In current sequencing of new tumors with the goal of neoantigen identification such mRNA expression studies are routine and allow routine verification of presence of mutant alleles in the mRNA pool. 
     Filtering for peptide presence orfeome—Since for a small percentage of genes, different isoforms can actually make use of the shifted reading frame, or by chance a 10-mer could be present in any other gene, we verified the absence of any picked peptide from peptides that can be defined in any entry of the reference sequence collection, once converted to a collection of tiled 10-mers. 
     Generation of cohort coverage by all peptides per gene To generate overviews of the proportion of patients harboring exhaustive FS peptides starting from the most mentioned gene, we first pooled all peptides of size 10 by gene and recorded the largest group of patients per tumor entity. Subsequently we picked peptides identified in the largest set of patients and kept on adding a new peptide in descending order, but only when at least 1 new patient was added. Once all patients containing a peptide in the first gene was covered, we progressed to the next gene and repeated the procedure until no patient with FS mutations leading to a peptide of size 10 was left. 
     proto-NOP (pNOP) and Neo-ORFeome proto—NOPs are those peptide products that result from the translation of the gene products when the reading frame is shifted by −1 or +1 base (so out of frame). Collectively, these pNOPs form the Neo-Orfeome. As such we generated a pNOP reference base of any peptide with length of 10 or more amino acids, from the RefSeq collection of sequences. Two notes: the minimal length of 10 amino acids is a choice; if one were to set the minimal window at 8 amino acids the total numbers go up a bit, e.g. the 30% patient covery of the library goes up. On a second note: we limited our definition to ORFs that can become in frame after a single insertion deletion on that location; this includes obviously also longer insertion or deletion stretches than +1 or −1. The definition has not taken account more complex events that get an out-of-frame ORF in frame, such as mutations creating or deleting splice sites, or a combination of two frame shifts at different sites that result in bypass of a natural stop codon; these events may and will occur, but counting those in will make the definition of the Neo-ORFeome less well defined. For the magnitude of the numbers these rare events do not matter much. 
     Visualizing nops—Visualization of the nops was performed using custom perl scripts, which were assembled such that they can accept all the necessary input data structures such as protein sequence, frameshifted protein sequences, somatic mutation data, library definitions, and the peptide products from frameshift translations. 
     Detection of frameshift resulting neopeptides in uterine cancer patients with cancer predisposition mutations—Somatic and germline mutation data were downloaded from the supplementary files attached to the manuscript posted here: https://www.biorxiv.org/content/biorxiv/early/2019/01/16/415133.full.pdf. Frameshift mutations were selected from the somatic mutation files and out-of-frame peptides were predicted using custom Perl and Python scripts, based on the human reference genome GRCh37. Out-of-frame peptides were selected based on their length (&gt;=10 amino acids) and mapped against out of frame peptide sequences for each possible alternative transcript for genes present in the human genome, based on Ensembl annotation (ensembl.org). 
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