bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3387: Comprehensive detection and analysis of mutant-SF3B1 splice pattern
Authors: Alsafadi Samar , Bellanger Dorine , Cornella Michele , Lehnert Erik , Roman-Roman Sergio , Stern Marc-Henri , Popova Tatiana 
Published: August 2019

Abstract
Aberrant alternative splicing is emerging as a frequent and important process in cancer. Splice aberrations are mainly associated with missense mutations within genes encoding splice factors involved in 3′-splice site recognition. SF3B1, U2AF1, SRSF2 and ZRSR2 are the most frequently mutated genes encoding splicing factors in tumors. Interestingly, these mutations are mutually exclusive and each leads to a distinct aberrant splice pattern.
Based on RNA-seq analyses of 74 primary tumors of uveal melanoma, we previously defined the aberrant splice pattern of SF3B1 hotspot mutations. In order to further characterize the catalogue of pathogenic mutations in SF3B1 that induce the aberrant splice pattern, we used a Sequence Bloom Tree (SBT) constructed from RNA-seq data for a total of 11,350 different tumors from the TCGA (Collaborative project with Seven Bridges Cancer Genome Cloud) to rapidly screen for samples consistent with the aberrant splice pattern.
Based on this analysis, 75 tumors from different tissues of origin presented with the mutant-SF3B1 pattern, including 70 tumors harboring SF3B1 mutations: 48 cases of the hotspot mutations (21 tumors with SF3B1R625, 6 with SF3B1K666 and 21 with SF3B1K700) and 22 cases harbored non-hotspot SF3B1 mutations. No mutation or deletion in SF3B1 was detected in 5 tumors. Taking into account that the threshold of scores defining the significant presence of the aberrant splice pattern varies between tumor types, we proceeded to an in cellulo validation of a set of newly described mutations of SF3B1 and confirmed the induction of the aberrant splice pattern.
Overall, our study highlights the potential of splice patterns as a biomarker in absence of detectable splice related mutations and sheds light on an efficient, large-scale computational approach to screen clinical cases for splice patterns.
Citation Format: Samar Alsafadi, Dorine Bellanger, Michele Cornella, Erik Lehnert, Sergio Roman-Roman, Marc-Henri Stern, Tatiana Popova. Comprehensive detection and analysis of mutant-SF3B1 splice pattern [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3387.
Abstract 3388: Tumor suppressor genes may promote tumorigenesis through allele specific expression
Authors: Clayton Evan 
Published: August 2019

Abstract
Cancer has long thought to be a disease which develops from de novo cancer driver mutations in oncogenes and tumor suppressor genes (TSGs). The purpose of our study is to examine how TSGs contribute to tumorigenesis. Accordingly, we studied loss-of-function (LoF) mutations in TSGs within 2504 individuals from 1000 Genomes Project (1KGP) and 233 patients across four different cancer types from The Cancer Genome Atlas (TCGA). We found a large fraction of 1KGP individuals were carriers of heterozygous LoF mutations in TSGs. However, compound heterozygosity of LoF mutations in at least one TSG was only found in 20% of our TCGA patients. Further, analysis of allele specific expression (ASE) in these tumors identified several TSGs where the mutant allele is overexpressed relative to the reference allele. This evidence of ASE suggests TSGs have the potential to drive tumorigenesis in the heterozygous condition, if the reference allele is sufficiently repressed.
Citation Format: Evan Clayton. Tumor suppressor genes may promote tumorigenesis through allele specific expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3388.
Abstract 3397: The mechanism of PI3K activation at the atomic level
Authors: Zhang Mingzhen , Jang Hyunbum , Nussinov Ruth 
Published: August 2019

Abstract
PI3Ks are a family of lipid kinases in the PI3K/Akt/mTOR pathway that regulates cellular processes. PI3Kα harbors the frequent somatic oncogenic driver mutations conferring gain of function. It is an obligate heterodimer with the regulatory p85α subunit and catalytic p110α subunit. Here, we determine the PI3Kα activation mechanism by nSH2 release at the atomic resolution. The PIP2 substrate binding site is far from ATP and the membrane binding surface is buried in the inactive PI3Kα, raising the question of how catalysis is executed. Our results show that release of nSH2 domain from PI3Kα triggers significant conformational change in p110α, exposing kinase domain for membrane interaction. The C-lobe of kinase domain shows the structural rearrangement to reduce the distance between the ATP and the substrate binding site, offering an explanation to how phosphoryl transfer is executed. This explains how oncogenic mutations promote PI3Kα activation by facilitating nSH2 release and offers an innovative, PI3K isoform-specific drug discovery principle that prevents substrate phosphorylation by targeting isoform-specific residues in the substrate binding site.
Citation Format: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. The mechanism of PI3K activation at the atomic level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3397.
Abstract 3414: Identifying dysregulated lncRNAs and miRNAs in low grade glioma: Uncovering signaling pathways and novel therapeutic targets
Authors: Carney Stephen , Nuñez Felipe , Lowenstein Pedro R. , Castro Maria G. 
Published: August 2019

Abstract
A molecular subtype of low grade gliomas (LGG) is characterized by mutations in Alpha-Thalassemia Mental Retardation X-linked (ATRX), TP53 and isocitrate dehydrogenase 1 (IDH1R132H, mIDH1). Our lab has generated a genetically engineered mouse model that harbors the characteristic genetic lesions found in this molecular subtype of LGG. We determined that mouse neurospheres (NS) bearing these mutations showed downregulation of signaling pathways involved in oligodendrocyte differentiation. The production of 2-hydroxyglutarate (2HG) by mIDH1 induces histone and DNA hypermethylation, which has been shown to impair neural precursor cells’ differentiation. We aim to investigate how the presence of mIDH1 impacts the epigenetic regulation of long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs in human mutant IDH1 glioma cell cultures obtained from patients at the time of surgery. We hypothesize that the dysregulation/remodeling of lncRNAs, miRNAs and mRNAs contributes to the invasiveness, differentiation status and stemness of glioma cells. Only a handful of lncRNAs have been studied in relation to their role in neural cells’ lineage commitment and glioma stem cells’ biology. We identified 127 differentially expressed (DE) lncRNA (FDR&lt;0.01) in a human primary glioma cell culture SJGBM2, which has a ATRX mutation and was stably-transfected to express mIDH1. Of the 14 DE miRNAs identified, hsa-miR-210-3p and hsa-miR-4461, which have been linked to tumor invasiveness. The results from this work will reveal novel mechanistic pathways by which lncRNA/miRNAs and differentially expressed mRNAs impact downstream signaling pathways in LGG and uncover new therapeutic targets for this molecular glioma subtype.
SC is supported by the T32 Cancer Biology Training Grant, the work is supported by grants from NIH/NINDS to MGC and PRL.
Citation Format: Stephen Carney, Felipe Nuñez, Pedro R. Lowenstein, Maria G. Castro. Identifying dysregulated lncRNAs and miRNAs in low grade glioma: Uncovering signaling pathways and novel therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3414.
Abstract 3417: Genomic analyses of clear cell papillary kidney cancers reveal large metabolic alterations and activation of the hypoxia pathway
Authors: Lindgren David , Sjolund Jonas , Nilsson Helen , Ljungberg Borje , Johansson Martin , Axelson Hakan 
Published: August 2019

Abstract
Tumors arising from the nephron of the kidney are collectively called renal cell carcinomas (RCCs). Recent high-throughput genomics endeavors, such as the TCGA initiative, have provided a roadmap for a deepened molecular understanding of these tumor types. With the aim to characterize RCCs that do not conform to the most common subtypes of RCC we scrutinized RNA-Seq transcriptomes of kidney tumor samples supplied by the TCGA project. Dimensionality reduction analyses revealed one defined a transcriptional subset of RCCs, which upon re-review of tissue histology could be classified as clear cell papillary RCC (ccpRCC). In line with previous analyses, samples were defined by overexpression of KRT7, CA9, CCND1 and GATA3 and harbored few genomic alterations as well as a limited number of gene mutations; only mTOR was found recurrently mutated. We observed upregulation of the Hypoxia inducible factor (HIF) pathway, possibly caused by VHLinactivation by gene promoter methylation in the majority of ccpRCCs. This may explain the morphological resemblance of ccpRCCs to VHL driven conventional clear cell RCCs. Further, the methylomes of ccpRCCs were distinct from other tumors and transcription factors specific for epithelial cells of the distal nephron were overexpressed, thus suggesting distinct tumor ontogeny of ccpRCCs compared to other renal tumors.
Citation Format: David Lindgren, Jonas Sjolund, Helen Nilsson, Borje Ljungberg, Martin Johansson, Hakan Axelson. Genomic analyses of clear cell papillary kidney cancers reveal large metabolic alterations and activation of the hypoxia pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3417.
Abstract 3421: Comparison of mutations in different subtypes of sarcomas and its clinical implications
Authors: Song Xinghua , Lian Zuping , Xiao YanBin , Bu Kunpeng , Qiu Ye , Ji Tao , Liu Dan , Liu Angen , Wang Kai 
Published: August 2019

Abstract
Background:
Sarcoma is a malignant cancer that arises from transformed cells of mesenchymal origin. Sarcoma has the characteristics of low incidence and wide distribution of onset age. Sarcoma patients have poor prognosis and very limited selection of approved targeted drugs. Till now, the genomic features of sarcoma patients in China have not been well understood. Here we present the comprehensive genomic features of 202 sarcoma patients and compared mutations in different subtypes of sarcomas.
Methods:
Deep sequencing targeting 450 cancer genes was performed on FFPE and matched blood samples collected from 202 sarcoma patients. Based on the histology patients included 33 osteosarcoma (OS), 24 rhabdomyosarcoma (RMS), 20 liposarcoma (LPS), 19 fibrosarcoma (FBS), 16 leiomyosarcoma (LMS), 14 Ewing’s sarcoma (ES), 11 hemangiosarcoma (HMS), 10 synovial sarcoma (SS), 9 chondrosarcoma (CDS), and 46 others in this study. Genomic alterations (GAs) including single nucleotide variants (SNVs), insertions and deletions, copy number variations (CNV) and fusions were assessed.
Results:
Based on the deep sequencing results, there are 1219 somatic mutations detected in all 202 sarcomas, average 6.0 mutations per sample. The most common GAs of LPS, ES and SS’s are consistent with those mentioned in NCCN guidelines (MDM2 55%, EWSR1 78.6% and SS18 80%, respectively). OS, RMS and LMS shared the same most common GAs of TP53 (25%-50%). The second ranked common GAs were NCOR1 (24%), FRS2 (20.8%), ATRX (25%) genes, and the third ranked GAs were RB1 (24%), CDK4 (16.7%) and MAP2K4 (25%) genes. 161/202 patients (79.7%) harbored at least one actionable mutations which might benefit from FDA approved drugs or drugs were under investigation in clinical trials. All FBS, 93.8% LMS and 90.9% HMS have actionable mutations, however, only 10% SS and 35.7% ES have actionable mutations. 8 samples have CNV (including MDM2/4, EGFR and CCND1) which was related to hyper-progression of immunotherapy. All these 8 samples were bone tumor including 4 OS, 1 CDS, 2 ES and 1 fibrosarcoma of bone.
Conclusions:
Through the comprehensive genomic profiling, different types of sarcomas showed different characteristics of genomic alterations, and potential therapeutic targets may be identified for the patients. Further, NGS provides information on whether or not patients may have the potential hyper-progression of immunotherapy.
Citation Format: Xinghua Song, Zuping Lian, YanBin Xiao, Kunpeng Bu, Ye Qiu, Tao Ji, Dan Liu, Angen Liu, Kai Wang. Comparison of mutations in different subtypes of sarcomas and its clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3421.
Abstract 3427: Exome sequencing of primary papillary thyroid cancer and their distant metastases reveals the role of DNA methylation and transcriptional repression genes
Authors: Masoodi Tariq , Siraj Abdul K. , Siraj Sarah , Azam Saud , Qadri Zeeshan , Albalawy Wafaa N. , Parvathareddy Sandeep Kumar , Al-Sobhi Saif S. , Al-Dayel Fouad , Alkuraya Fowzan S. , Al-Kuraya Khawla S. 
Published: August 2019

Abstract
Distant metastasis is a rare occurrence in thyroid cancer, associated with dismal prognosis. The genomic repertoires of various solid malignancies have previously been reported but remain under-explored in metastatic Papillary Thyroid Cancer (PTC). Furthermore, whether distant metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole exome sequencing on 14 matched distant metastases, primary PTC tumors and normal tissues. Point mutations, copy number alterations, cancer cell fractions and mutation signatures were defined using state-of-the-art bioinformatics methods. All likely deleterious variants were validated by orthogonal methods. Genomic differences were observed between primary and distant metastatic deposits with a median of 62% (range 21% - 92%) of somatic mutations detected in metastatic tissues, but absent from the corresponding primary tumor sample. Mutations in known driver genes including BRAF, NRAS and HRAS were shared and preferentially clonal in both sites. On the other hand, likely deleterious variants affecting DNA methylation and transcriptional repression signaling genes including SIN3A, RBBP1 and CHD4 were found to be restricted in the metastatic lesions. Moreover, mutational signature shift was observed between the mutations that are specific or enriched in the metastatic and primary lesions. Primary PTC and distant metastases differ in their range of somatic alterations. Genomic analysis of distant metastases provides an opportunity to identify potentially clinically informative alterations not detected in primary tumors, which might influence decisions for personalized therapy in PTC patients with distant metastasis.
Citation Format: Tariq Masoodi, Abdul K. Siraj, Sarah Siraj, Saud Azam, Zeeshan Qadri, Wafaa N. Albalawy, Sandeep Kumar Parvathareddy, Saif S. Al-Sobhi, Fouad Al-Dayel, Fowzan S. Alkuraya, Khawla S. Al-Kuraya. Exome sequencing of primary papillary thyroid cancer and their distant metastases reveals the role of DNA methylation and transcriptional repression genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3427.
Abstract 3428: The landscape of germline mutations in Chinese patients with solid tumor
Authors: Li Juming , Wei Yongzhong , Chen Xiaoqian , Liu Angen , Shi Junping , Hu Jinwei , Yao Ming 
Published: August 2019

Abstract
Background: Germline mutations harbored by cancer patients can be passed from parents on to offspring, which increases the tumor risk in offspring as well. Therefore, investigating the germline mutations in cancer patients has important clinical implications for treatment selection and familial cancer risk assessment.
Methods: FFPE tumor and matched blood samples were collected from 3645 Chinese patients with solid tumors for next generation sequencing analysis. The NGS panel targeted 450 cancer genes, 47 of these genes were tumor inheritance susceptibility genes that were mentioned by NCCN guidelines. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indel), copy number variations (CNV) and gene rearrangements and fusions were assessed.
Results:Germline mutations were identified in 241 of 3645 Chinese patients with solid tumor (6.6%). The patients with germline mutations included 137 males and 104 females with a median age of 54. Tumor types with higher frequency of germline mutations were: ovarian cancer (22.0%), breast cancer (13.4%), pancreatic cancer (9.9%), cholangiocarcinoma (8.6%), small intestinal cancer (8.6%), colorectal cancer (8.6%), soft tissue sarcoma (6.3%), uterine Cancer (5.9%), gastric cancer (5.8%) and bone cancer (5.1%). The distribution of germline mutations were 14.1% in BRCA1, 13.7% in BRCA2, 10.8% in SPINK1, 9.1% in ATM, 5.8% in RAD50, 4.6% in PALB2, 3.7% in BARD1 and FANCA, 3.3% in MSH6 and 2.9% in MLH1, respectively. The types of germline mutations were SNVs and short Indels, but no long Indels, CNV, gene rearrangements or fusions were observed. The percentage of patients with a family history was 27.4%, without family history was 52.7%, unknown was 19.9%.
Conclusions:Our data revealed that germline mutations occurred in 6.6% of Chinese solid tumor patients. Gynecological tumor, gastrointestinal tumor, bone and soft tissue tumor are the most common types of tumors that harbored germline mutations. The most common mutant genes were HRD (64.5%) and MMR (10.5%) related genes. More than 50% patients with germline mutations had no family history, which suggests the importance of germline mutations detection for all solid tumor patients to verify if there is a risk of genetic transmission to offspring. NGS based panel sequencing showed the advantage of identifying solid tumor patients with germline mutations, and provided the information of familial cancer risk assessment and guided the precise cancer treatment options.
Citation Format: Juming Li, Yongzhong Wei, Xiaoqian Chen, Angen Liu, Junping Shi, Jinwei Hu, Ming Yao. The landscape of germline mutations in Chinese patients with solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3428.
Abstract 3445: Mechanism, physiological and therapeutic implications of LGR-independent potentiation of WNT signaling by R-spondins
Authors: Lebensohn Andres M. , Rohatgi Rajat 
Published: August 2019

Abstract
The WNT signaling pathway encodes positional information in animals, orchestrates patterning and morphogenesis during embryonic development, and promotes tissue renewal and regeneration in adults. Dysregulation of WNT signaling has been implicated in many diseases, including developmental malformations, skeletal and dental abnormalities, cardiovascular and neurodegenerative disorders, diabetes, and many types of cancer. Members of the R-spondin family of secreted growth factors have emerged as key regulators of WNT signaling strength. The R-spondin system is a vertebrate adaptation that may be related to the appearance of sophisticated stem cell compartments, which require exquisite control of WNT signaling. The four members of the family (R-spondin 1-4) can strongly potentiate responses to WNT ligands during development and in stem cells, but the mechanisms by which they transduce signals are not fully understood and the reasons why they produce different physiological effects are largely unknown. Unexpectedly, we discovered that R-spondins 2 and 3 can uniquely potentiate WNT signaling in cells lacking LGRs 4, 5 and 6, the principal R-spondin receptors. We determined the protein domains on R-spondins necessary and sufficient for this new mode of signaling, and showed that it is mediated by an alternative interaction with cell-surface heparan sulfate proteoglycans. This finding is transformative because LGRs 4-6 were thought to be required to transduce all R-spondin signals and hence determine their site of action. Indeed, these LGRs are highly expressed in many stem cell compartments whose maintenance depends on potentiation of WNT signaling by R-spondins. Instead our work shows that there are two modes of signaling by R-spondins, an LGR-dependent and an LGR-independent mode, and that different R-spondins may use distinct molecular mechanisms to transduce signals in various biological contexts. Supporting our findings, recent work from another group demonstrated that during limb development, R-spondin 2 signals through an LGR-independent mechanism. Since components of the R-spondin signaling module are commonly mutated in cancer, therapeutic targeting of LGR-independent signaling deserves evaluation. I will present the results demonstrating our conclusions and discuss their implications in physiology and disease.
Citation Format: Andres M. Lebensohn, Rajat Rohatgi. Mechanism, physiological and therapeutic implications of LGR-independent potentiation of WNT signaling by R-spondins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3445.