bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3285: COSMIC-3D: Impacts of cancer mutations on protein structure, function, and druggability
Authors: Jubb Harry C. , Saini Harpreet K. , Verdonk Marcel L. , Forbes Simon A. 
Published: August 2018

Abstract
In recent years there has been an explosion in cancer genomic data that has enabled understanding of the incidence and patterns of mutations in cancer patients. The challenge is to translate this vast resource of genomic research and data into precision medicines that target specific mutations in patient populations and improve clinical outcomes. Delivering personalised cancer medicines requires greater understanding of how cancer mutations impact the structure, function, and druggability of known and potential protein drug targets.
In this study we annotate each missense mutation in COSMIC, via COSMIC-3D (http://cancer.sanger.ac.uk/cosmic3d), with protein structural features derived from the wwPDB, and rich functional features derived from the UniProt protein database. The structural features include small molecule binding sites (including drug binding sites), protein-protein interaction interfaces, protein-nucleic acid interactions, solvent inaccessible protein “core” versus solvent exposed areas, and predicted small-molecule druggability. The UniProt-derived functional features represent high quality functional site annotations, including post-translational modification sites, functional domains and motifs, and regions of biological interest.
In addition, we explore the relationship between mutation occurrence in protein structural and functional sites, and recurrence in cancer. We found that recurrent missense mutations are significantly enriched in specific structural and functional environments, including small-molecule binding sites and predicted druggable pockets. These results provide promising hypotheses that recurrent, cancer driving mutations may be targeted by small-molecule drugs. We posit that further characterisation of the structure-function implications of each mutation in COSMIC-3D will increasingly aid mutation-guided target discovery and drug design.
Citation Format: Harry C. Jubb, Harpreet K. Saini, Marcel L. Verdonk, Simon A. Forbes. COSMIC-3D: Impacts of cancer mutations on protein structure, function, and druggability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3285.
Abstract 3286: A prototype Cancer Publication Portal (CPP) for summarizing and accessing cancer genomic publications
Authors: Johnson Andrew , DePratti Roland , Dancik Garrett M. 
Published: August 2018

Abstract
A search of PubMed finds more than 71,000 publications with the keywords “cancer” and “gene” published since the beginning of 2015. This increasingly large volume of publications necessitates the development of text-mining tools to help cancer researchers navigate and summarize articles efficiently. Here, we present a prototype Cancer Publication Portal (CPP) that allows a user to search and summarize the biomedical literature for a gene of interest. CPP leverages the data generated by PubTator, a tool that uses robust text-mining methods and associates articles with gene names and Medical Subject Heading (MeSH) terms. Additionally, CPP associates articles with therapeutic agents and selected cancer-related terms from the NCI Thesaurus. To use CPP, the user selects a gene of interest, and is presented with a summary of MeSH terms, therapeutic agents, and cancer-related terms that are associated with the selected gene. Cancer-related terms are highlighted, so that, for example, a user can quickly ascertain the frequency of publications per cancer type, or how many articles are associated with “mutations” in the gene. The summaries are interactive, so that the user can click on a term of interest to filter the results, and update the summaries. The user can repeat this process to narrow in on a specific topic of interest. Following all searches and filters, relevant articles are listed and are linked back their PubMed entries so that the reference article can be accessed. CPP currently includes information for ~4 million publications associated with &gt;10,000 human genes. The underlying data is stored in an Oracle database while R/Shiny is used to implement the web interface. CPP is available from the following link: https://gdancik.github.io/bioinformatics/
Citation Format: Andrew Johnson, Roland DePratti, Garrett M. Dancik. A prototype Cancer Publication Portal (CPP) for summarizing and accessing cancer genomic publications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3286.
Abstract 3294: Functional annotation for alternative splicing to investigate disrupted splicing in cancer
Authors: Hyung Daejin , Kim Jihyun , Cho Soo Young , Park Charny 
Published: August 2018

Abstract
Alternative splicing (AS) plays a key role to confer human genome complexity. The advent of mRNA high-throughput sequencing facilitates to identify precise differential alternative splicing analysis. Massive result estimated from RNA-Seq should be sorted out whether AS has functional impact or not. Previous studies investigated protein domain or nonsense-mediated decay of AS event region. However other functional sites on exon inclusion region also exist. For example, miRNA binding site, and post-translational modification of AS site already are reported to assign functional impact. Therefore we developed ASpedia (http://combio.snu.ac.kr/aspedia/) to annotation functional impact of AS event. AS events of our database were generated from human genome hg19 ENSEMBL and Refseq. ASpedia provides a database, explore system, and AS browser to annotate functional impact evidence encompassing DNA, RNA, and protein. The user could query multiple AS events from differential AS analysis result. Currently our system supports a jar execution file to convert input query file from MISO or rMATS result.
The variant of splicing factor (SF) disrupts normal splicing. It could be assumed that target genes of mutated SF could be transcribed to aberrant isoforms by changed splicing machinery. Therefore we investigated the comprehensive SF variant status from TCGA somatic mutation and copy number. SF3B1 (2% in BRCA) and U2AF1 (4% in AML, and 2% in LUAD) were shown to recurrent mutation including hotspot. ELAVL2 known dispensable splicing factor to brain tissue were highly recurrent in deletion (18% in GBM). In order to examine aberrant AS events caused SF variants, we estimated exon-inclusion proportion Percent-Spliced-In (PSI) values for identifiable AS events using TCGA RNA-Seq dataset. Using differentially AS event analysis, we identified AS events that were significantly differentially spliced in the presence of a U2AF S34F/Y mutation (119 in AML). And we purposed to finding In order to investigate functional site, the differentially spliced AS events were additionally annotated using ASpedia. Finally we identified the landscape of that AS events were altered by SF variants, and we proved that a part of the events was involved in cancer-associated functions.
Citation Format: Daejin Hyung, Jihyun Kim, Soo Young Cho, Charny Park. Functional annotation for alternative splicing to investigate disrupted splicing in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3294.
Abstract 3301: Using a novel single-cell lineage-tracing technique to uncover the mechanisms driving nongenetic cancer relapse
Authors: Oren Yaara , Regev Aviv , Brugge Joan 
Published: August 2018

Abstract
Despite favorable initial response to platinum chemotherapy, the majority of patients with ovarian cancer will develop recurrent disease and succumb to it within 5 years of diagnosis. Initial recurrence is frequently platinum-sensitive and women can respond to multiple lines of platinum-based chemotherapy before eventually developing platinum-refractory disease. The observation that the tumor cells that survive the initial therapy give rise to a chemosensitive progeny is inconsistent with a simple Darwinian model of selection of genetically resistant clones. Tumor dormancy, stochastic cell state shifts and stem cell-like populations are among the mechanisms hypothesized to mediate re-emergence of platinum-sensitive ovarian cancer. However, given the lack of high-throughput methods to simultaneously track cell state and lineage, it is not currently feasible to distinguish the relative contribution of each of these factors. To address this need, we generated a new lentiviral barcode library, termed Watermelon. Unlike existing barcoding libraries that enable the tracking of multiple cancer cells solely at the DNA level, the Watermelon library encodes transcribed barcodes, which allows one to map the lineage to the transcriptional profile of each individual cell. This unique barcoding scheme, which is coupled with a genetic H2B retention system, enables simultaneous tracing of lineage as well as the transcriptional and proliferative states of each cell in the population during drug treatment. We have established and characterized an in vitro platinum-sensitive relapse model and are applying the Watermelon system together with time-lapse imaging to study the mechanisms underlying time-to-relapse variation and cell-fate decisions. By broadening our knowledge of the cellular and molecular pathways that affect noninherited drug resistance, our work will facilitate the future development of novel therapies that delay or even prevent the emergence of platinum-refractory ovarian cancer.
Citation Format: Yaara Oren, Aviv Regev, Joan Brugge. Using a novel single-cell lineage-tracing technique to uncover the mechanisms driving nongenetic cancer relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3301.
Abstract 3305: Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal adenomas and carcinomas
Authors: Bormann Felix , Rodríguez-Paredes Manuel , Lasitschka Felix , Edelmann Dominic , Benner Axel , Bergman Yehudit , Ball Claudia R. , Glimm Hanno , Linhart Heinz G. , Lyko Frank 
Published: August 2018

Abstract
Introduction: Colorectal adenomas are precursor lesions of colorectal cancers and represent clonal amplifications of single cells from colonic crypts. DNA methylation patterns specify cell-type identity during cellular differentiation and therefore provide novel opportunities for tumor subclassification and patient stratification.
Methods: Infinium 450k and EPIC data from of non-malignant colorectal adenomas was applied to a consensus clustering algorithm. This defined epigenetic subtypes that were subsequently tested for clinico-pathological features, such as morphology and mutation status. Additionally, the subtypes were compared with Infinium 450k data from colonic crypt sections and also colorectal cancer samples provided by The Cancer Genome Atlas. Finally, clinical significance was addressed by testing for subtype specific overall survival rates.
Results: The analysis of the adenoma dataset defined 3 distinct epigenetic subtypes of human premalignant lesions. These 3 subtypes also reflect 3 of 4 epigenetic subtypes identified in colorectal cancer. The fourth, cancer-specific subtype represents the previously known subclass defined by microsatellite instability phenotype and the CpG island methylator phenotype. Comparisons to Crypt section methylomes and to other reference methylomes revealed that the other 3 subtypes represent epigenetic programs reflecting various intestinal crypt cell differentiation stages. Patient survival correlated with the differentiation stages with a particular poor prognosis for patients with stem cell-related epigenetic signatures.
Conclusion: Our results establish a novel and clinically relevant approach for colorectal adenoma and cancer classification and illustrate how differences in the cell-type of origin shape the tumor methylome.
Citation Format: Felix Bormann, Manuel Rodríguez-Paredes, Felix Lasitschka, Dominic Edelmann, Axel Benner, Yehudit Bergman, Claudia R. Ball, Hanno Glimm, Heinz G. Linhart, Frank Lyko. Cell-of-origin differentiation stages define methylation-based subtypes of human colorectal adenomas and carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3305.
Abstract 3310: Non-invasive diagnosis of colorectal cancer via targeted high-throughput DNA methylation sequencing of circulating tumor DNA (ctDNA)
Authors: Wu Xianrui , Chuan Jiacheng , Hu Tuo , Peng Tingting , Yang Meng , Shen Hui , Laird Peter , Gao Yangbin , Cai Xuyu , Xu Weihong , Fan Jian-bing , Lan Ping 
Published: August 2018

Abstract
Colorectal cancer (CRC) commonly develops from precancerous polyps. Most polyps are benign. The current screening method involves stool tests and colonoscopy, which is an unpleasant procedure. Even though stool DNA-based approach has been developed, it is still a clinical challenge to differentiate benign complications and malignant CRC.
We took the approach of high-throughput DNA bisulfide sequencing of tissue samples to identify cancer-specific methylation signatures. We learned methylation patterns by in-depth data mining and then applied pattern recognition approach to classify plasma samples. From a cohort of 70 pairs of tumor-normal matched tissue samples, we identified 1062 differential methylation markers. Next, we applied a greedy optimization algorithm to build a malignancy classification model using a training set of 118 plasma samples (malignant CRC: 56, benign complications: 23, healthy subjects: 39). In the training set, we achieved an AUC of 91.9% (95%CI: 87.3-96.5%). In an independent test set of 150 plasma samples (malignant CRC: 56, benign complications: 23, healthy subjects: 71), we achieved an AUC of 92.9% (95%CI: 88.3%~97.5%). Specifically, the model had a sensitivity of 91.1% for the identification of malignant CRC, and a specificity of 84.5% and 78.3% for healthy subjects and benign complications respectively. Our assay was demonstrated to be very sensitive towards early-stage CRC detection, with a sensitivity of 76.5% and 95% for stage I and II CRC respectively. The performance of this assay still awaits further validation in a large-scale clinical trial.
In summary, we have developed a highly sensitive blood-based non-invasive diagnostic assay for the identification of malignant CRC, which can aid clinical decisions for doctors. This approach can also be extended to non-invasive early screening for various other cancer types.
Citation Format: Xianrui Wu, Jiacheng Chuan, Tuo Hu, Tingting Peng, Meng Yang, Hui Shen, Peter Laird, Yangbin Gao, Xuyu Cai, Weihong Xu, Jian-bing Fan, Ping Lan. Non-invasive diagnosis of colorectal cancer via targeted high-throughput DNA methylation sequencing of circulating tumor DNA (ctDNA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3310.
Abstract 332: The BET bromodomain inhibitor JQ1 synergizes with WEE1 inhibitor AZD1775 by impairing non-homologous end joining and enhancing DNA damages in non-small cell lung cancer
Authors: Takashima Yuta , Kikuchi Eiki , Kikuchi Junko , Shoji Tetsuaki , Furuta Megumi , Kikuchi Hajime , Sakakibara-Konishi Jun , Kinoshita Ichiro , Dosaka-Akita Hirotoshi , Nishimura Masaharu 
Published: August 2018

Abstract
Background: The bromodomain and extraterminal domain (BET) inhibitors are broadly active in different cancer types, including non-small cell lung cancer (NSCLC). Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the mechanism of BET inhibition on the cytotoxicity remain unknown. BET proteins have been also reported to interact with some DNA damage repair-related genes. AZD1775, a selective WEE1 G2 checkpoint kinase inhibitor, induces DNA damage and consequent apoptosis by abrogating G2 cell cycle arrest and inducing premature mitotic entry. We hypothesized that repression of BET activity would increase WEE1 inhibitor-induced cytotoxicity by impairing DNA damage repair. Here, we evaluate the efficacy and mechanistic rationale for combining AZD1775 and JQ1 as a potential therapy for NSCLC.
Methods: NSCLC cell lines (A549, H1299, H1975) and human embryonic kidney cells line (293T) were used in the present study. Anti-tumor activities of JQ1, AZD1775, or the combination were analyzed using MTT survival assay. Changes in protein expression were analyzed by Western Blot analysis. mRNA expressions were evaluated by quantitative rt-PCR. Cell cycle was analyzed by flow cytometry using PI staining. Activity of non-homologous end joining (NHEJ) was evaluated using NHEJ reporter plasmid.
Results: The combination of AZD1775 and JQ1 showed synergistic effects for NSCLC cell lines in vitro with combination indices of 0.1-0.5. The JQ1 monotherapy did not induce gamma-H2AX expression, but JQ1 increased and prolonged AZD1775-induced gamma-H2AX expression. The mRNA analysis showed that JQ1 significantly repressed NHEJ-related genes, such as XRCC4 and LIG4. Moreover, NHEJ reporter assay revealed JQ1 diminished NHEJ activity.
Conclusions: Our data demonstrate that the combination of JQ1 and AZD1775 has a synergistic effect against NSCLC cell lines via a mechanism of compromised DNA damage repair by JQ1. This combination therapy can be a novel therapeutic strategy for NSCLC.
Citation Format: Yuta Takashima, Eiki Kikuchi, Junko Kikuchi, Tetsuaki Shoji, Megumi Furuta, Hajime Kikuchi, Jun Sakakibara-Konishi, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura. The BET bromodomain inhibitor JQ1 synergizes with WEE1 inhibitor AZD1775 by impairing non-homologous end joining and enhancing DNA damages in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 332.
Abstract 3324: Diagnosis and prognosis of hepatocellular carcinoma with ctDNA methylation markers
Authors: Zhang Kang 
Published: August 2018

Abstract
Abstract
An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumor DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive “liquid biopsy” for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation markers by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumor DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P&lt;0.001) and was highly correlated with tumor burden, treatment response, and stage (P&lt;0.001). Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P&lt;0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.
Citation Format: Kang Zhang. Diagnosis and prognosis of hepatocellular carcinoma with ctDNA methylation markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3324.
Abstract 3333: Detection of IDH1 R132H mutation in situ in human astrocytoma and glioma FFPE samples
Authors: Li Na , Wang Mindy , Sun Hongzhe , Zhang Zhifu , Wang Xin , Park Emily , Ma Xiao-Jun , Monroe Robert 
Published: August 2018

Abstract
IDH1 and IDH2 mutations have been shown to be early events in gliomagenesis. IDH1 mutations are present in ~33% of gliomas and constitute ~90% of all IDH mutations. Approximately 88% of IDH1 mutations involve the substitution c.395G&gt;A leading to the R132H amino acid change. IDH1 mutations, including R132H, are important to recognize clinically as they are more frequent in younger patients and confer a survival advantage. Patients with IDH1 mutations show lower expression of the prognostic markers p53 and Ki-67 and achieve greater benefit from maximal tumor resection. In addition to their prognostic utility, IDH mutations including IDH1 R132H can be useful as diagnostic markers for low-grade gliomas. In difficult to diagnose glial lesions, the presence of IDH mutations strongly favors a diagnosis of glioma versus reactive gliosis. Although PCR and DNA sequencing-based approaches can detect the IDH1 R132H mutation, these techniques require destruction of tissue for nucleic acid isolation and destroy the morphologic context, highlighting the need for a methodology that can be performed on formalin-fixed, paraffin-embedded (FFPE) tissues. In this study, we developed an assay to specifically detect the IDH1 R132H mutation in FFPE samples in expressed IDH1 mRNA transcripts using the novel BasescopeTM technology. IDH1 wild-type (WT) and IDH1 mutation (MT) probes were tested in 6 astrocytoma and 3 glioma FFPE specimens from unique clinical cases. All samples exhibited positivity with the IDH1 WT probe. Two of six astrocytomas and one of three gliomas showed positivity with the IDH1 R132H mutation probe. Among the three positive samples, one astrocytoma exhibited positive signals for the IDH1 R132H mutation in almost all tumor cells, whereas one astrocytoma and one glioma showed only scattered positive signals with the IDH1 R132H mutation probe in a subset of tumor cells. Our findings indicate that the BasescopeTM assay is a novel RNA in situ hybridization assay to visualize point mutations in a highly specific and sensitive manner within the morphologic tissue context. In this study, we demonstrate that the BasescopeTM IDH1 R132H assay is capable of detecting the IDH1 R132H mutation in routine FFPE clinical specimens for the purpose of assisting in the diagnosis of gliomas and providing prognostic information. The BasescopeTM technology also allows for correlation of the frequency and distribution of IDH1 R132H mutations in glial tumors with patient outcomes and overall survival.
Citation Format: Na Li, Mindy Wang, Hongzhe Sun, Zhifu Zhang, Xin Wang, Emily Park, Xiao-Jun Ma, Robert Monroe. Detection of IDH1 R132H mutation in situ in human astrocytoma and glioma FFPE samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3333.