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Grant Details

Grant Number: 4R01CA180006-04 Interpret this number
Primary Investigator: Ding, Li
Organization: Washington University
Project Title: Cancer Susceptibility Variant Discovery in High Throughput Sequencing Data
Fiscal Year: 2016
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Abstract

DESCRIPTION (provided by applicant): Large-scale cancer genomics projects such as The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and the Pediatric Cancer Genome Project (PCGP) are producing a wealth of high throughput sequence data from a large number of cancer samples and their matched normals. These data hold great promise for understanding the genetic basis of cancer and also for the identification of germline susceptibility variants in cancer. Major advancements have been made to systematically catalog somatic variations in cancer genomes from these data sets. However, identifying and interpreting germline changes using data from these studies remains a significant challenge. The primary difficulty stems from 1) the lack of computational pipelines/tools to utilize tumor and normal sequencing data for simultaneous detection of somatic, germline, and LOH events at the nucleotide and chromosomal levels and 2) the lack of uniform bioinformatics analysis strategies for identifying and prioritizing deleterious candidate germline variants responsible for susceptibility. We will develop a computational pipeline for the identification and interpretation f germline alterations in cancer including single nucleotide variants, insertions and deletions (indels), copy number variations, and structural variants. This pipeline will be initially used to systematically analyze whole genome, exome, and RNA-sequencing data from over 5,000 cancer cases already generated by several major efforts and individual research groups and additional cases that will be made publicly available in the next several years. In silico predicte deleterious germline variants from these data will be used for statistical association analysis across groups stratified by age and cancer type to identify novel germline susceptibility variants, genes, and pathways involved in different cancer types. We will further investigate the potential interaction between germline susceptibility variants and somatic mutational landscape. Finally, both pipeline and results from this project will be made publically available, facilitating the analysis and interpretation by the research community of the ever- growing large-scale cancer sequencing data to better discover and understand germline susceptibility variants.

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Publications

Integrative omics analyses broaden treatment targets in human cancer.
Authors: Sengupta S. , Sun S.Q. , Huang K.L. , Oh C. , Bailey M.H. , Varghese R. , Wyczalkowski M.A. , Ning J. , Tripathi P. , McMichael J.F. , et al. .
Source: Genome Medicine, 2018-07-27 00:00:00.0; 10(1), p. 60.
EPub date: 2018-07-27 00:00:00.0.
PMID: 30053901
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Pathogenic Germline Variants in 10,389 Adult Cancers.
Authors: Huang K.L. , Mashl R.J. , Wu Y. , Ritter D.I. , Wang J. , Oh C. , Paczkowska M. , Reynolds S. , Wyczalkowski M.A. , Oak N. , et al. .
Source: Cell, 2018-04-05 00:00:00.0; 173(2), p. 355-370.e14.
PMID: 29625052
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Comprehensive Characterization of Cancer Driver Genes and Mutations.
Authors: Bailey M.H. , Tokheim C. , Porta-Pardo E. , Sengupta S. , Bertrand D. , Weerasinghe A. , Colaprico A. , Wendl M.C. , Kim J. , Reardon B. , et al. .
Source: Cell, 2018-04-05 00:00:00.0; 173(2), p. 371-385.e18.
PMID: 29625053
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Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.
Authors: Gao Q. , Liang W.W. , Foltz S.M. , Mutharasu G. , Jayasinghe R.G. , Cao S. , Liao W.W. , Reynolds S.M. , Wyczalkowski M.A. , Yao L. , et al. .
Source: Cell Reports, 2018-04-03 00:00:00.0; 23(1), p. 227-238.e3.
PMID: 29617662
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Systematic Analysis of Splice-Site-Creating Mutations in Cancer.
Authors: Jayasinghe R.G. , Cao S. , Gao Q. , Wendl M.C. , Vo N.S. , Reynolds S.M. , Zhao Y. , Climente-González H. , Chai S. , Wang F. , et al. .
Source: Cell Reports, 2018-04-03 00:00:00.0; 23(1), p. 270-281.e3.
PMID: 29617666
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BreakPoint Surveyor: a pipeline for structural variant visualization.
Authors: Wyczalkowski M.A. , Wylie K.M. , Cao S. , McLellan M.D. , Flynn J. , Huang M. , Ye K. , Fan X. , Chen K. , Wendl M.C. , et al. .
Source: Bioinformatics (oxford, England), 2017-10-01 00:00:00.0; 33(19), p. 3121-3122.
PMID: 28582538
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GenomeVIP: a cloud platform for genomic variant discovery and interpretation.
Authors: Mashl R.J. , Scott A.D. , Huang K.L. , Wyczalkowski M.A. , Yoon C.J. , Niu B. , DeNardo E. , Yellapantula V.D. , Handsaker R.E. , Chen K. , et al. .
Source: Genome Research, 2017 Aug; 27(8), p. 1450-1459.
EPub date: 2017-05-18 00:00:00.0.
PMID: 28522612
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Proteogenomic Integration Reveals Therapeutic Targets In Breast Cancer Xenografts
Authors: Huang K.L. , Li S. , Mertins P. , Cao S. , Gunawardena H.P. , Ruggles K.V. , Mani D.R. , Clauser K.R. , Tanioka M. , Usary J. , et al. .
Source: Nature Communications, 2017-03-28 00:00:00.0; 8, p. 14864.
PMID: 28348404
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Ctcf Genetic Alterations In Endometrial Carcinoma Are Pro-tumorigenic
Authors: Marshall A.D. , Bailey C.G. , Champ K. , Vellozzi M. , O'Young P. , Metierre C. , Feng Y. , Thoeng A. , Richards A.M. , Schmitz U. , et al. .
Source: Oncogene, 2017-03-20 00:00:00.0; , .
PMID: 28319062
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The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis.
Authors: Jones K.B. , Barrott J.J. , Xie M. , Haldar M. , Jin H. , Zhu J.F. , Monument M.J. , Mosbruger T.L. , Langer E.M. , Randall R.L. , et al. .
Source: Oncogene, 2016-09-22 00:00:00.0; 35(38), p. 5021-32.
EPub date: 2016-09-22 00:00:00.0.
PMID: 26947017
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Protein-structure-guided discovery of functional mutations across 19 cancer types.
Authors: Niu B. , Scott A.D. , Sengupta S. , Bailey M.H. , Batra P. , Ning J. , Wyczalkowski M.A. , Liang W.W. , Zhang Q. , McLellan M.D. , et al. .
Source: Nature Genetics, 2016 Aug; 48(8), p. 827-37.
PMID: 27294619
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NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence.
Authors: Manda K.R. , Tripathi P. , Hsi A.C. , Ning J. , Ruzinova M.B. , Liapis H. , Bailey M. , Zhang H. , Maher C.A. , Humphrey P.A. , et al. .
Source: Oncogene, 2016-06-23 00:00:00.0; 35(25), p. 3282-92.
EPub date: 2016-06-23 00:00:00.0.
PMID: 26477312
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Systematic discovery of complex insertions and deletions in human cancers.
Authors: Ye K. , Wang J. , Jayasinghe R. , Lameijer E.W. , McMichael J.F. , Ning J. , McLellan M.D. , Xie M. , Cao S. , Yellapantula V. , et al. .
Source: Nature Medicine, 2016 Jan; 22(1), p. 97-104.
PMID: 26657142
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Patterns and functional implications of rare germline variants across 12 cancer types.
Authors: Lu C. , Xie M. , Wendl M.C. , Wang J. , McLellan M.D. , Leiserson M.D. , Huang K.L. , Wyczalkowski M.A. , Jayasinghe R. , Banerjee T. , et al. .
Source: Nature Communications, 2015-12-22 00:00:00.0; 6, p. 10086.
EPub date: 2015-12-22 00:00:00.0.
PMID: 26689913
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Germline Mutations in Predisposition Genes in Pediatric Cancer.
Authors: Zhang J. , Walsh M.F. , Wu G. , Edmonson M.N. , Gruber T.A. , Easton J. , Hedges D. , Ma X. , Zhou X. , Yergeau D.A. , et al. .
Source: The New England Journal Of Medicine, 2015-12-10 00:00:00.0; 373(24), p. 2336-46.
EPub date: 2015-12-10 00:00:00.0.
PMID: 26580448
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Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.
Authors: Ciriello G. , Gatza M.L. , Beck A.H. , Wilkerson M.D. , Rhie S.K. , Pastore A. , Zhang H. , McLellan M. , Yau C. , Kandoth C. , et al. .
Source: Cell, 2015-10-08 00:00:00.0; 163(2), p. 506-19.
PMID: 26451490
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Optimizing cancer genome sequencing and analysis.
Authors: Griffith M. , Miller C.A. , Griffith O.L. , Krysiak K. , Skidmore Z.L. , Ramu A. , Walker J.R. , Dang H.X. , Trani L. , Larson D.E. , et al. .
Source: Cell Systems, 2015-09-23 00:00:00.0; 1(3), p. 210-223.
PMID: 26645048
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Genome Modeling System: A Knowledge Management Platform for Genomics.
Authors: Griffith M. , Griffith O.L. , Smith S.M. , Ramu A. , Callaway M.B. , Brummett A.M. , Kiwala M.J. , Coffman A.C. , Regier A.A. , Oberkfell B.J. , et al. .
Source: Plos Computational Biology, 2015 Jul; 11(7), p. e1004274.
PMID: 26158448
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The genomic landscape of childhood and adolescent melanoma.
Authors: Lu C. , Zhang J. , Nagahawatte P. , Easton J. , Lee S. , Liu Z. , Ding L. , Wyczalkowski M.A. , Valentine M. , Navid F. , et al. .
Source: The Journal Of Investigative Dermatology, 2015 Mar; 135(3), p. 816-23.
PMID: 25268584
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Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.
Authors: Wong T.N. , Ramsingh G. , Young A.L. , Miller C.A. , Touma W. , Welch J.S. , Lamprecht T.L. , Shen D. , Hundal J. , Fulton R.S. , et al. .
Source: Nature, 2015-02-26 00:00:00.0; 518(7540), p. 552-5.
EPub date: 2015-02-26 00:00:00.0.
PMID: 25487151
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Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes.
Authors: Leiserson M.D. , Vandin F. , Wu H.T. , Dobson J.R. , Eldridge J.V. , Thomas J.L. , Papoutsaki A. , Kim Y. , Niu B. , McLellan M. , et al. .
Source: Nature Genetics, 2015 Feb; 47(2), p. 106-14.
PMID: 25501392
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Age-related mutations associated with clonal hematopoietic expansion and malignancies.
Authors: Xie M. , Lu C. , Wang J. , McLellan M.D. , Johnson K.J. , Wendl M.C. , McMichael J.F. , Schmidt H.K. , Yellapantula V. , Miller C.A. , et al. .
Source: Nature Medicine, 2014 Dec; 20(12), p. 1472-8.
PMID: 25326804
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Comprehensive molecular characterization of gastric adenocarcinoma.
Authors: Cancer Genome Atlas Research Network .
Source: Nature, 2014-09-11 00:00:00.0; 513(7517), p. 202-9.
EPub date: 2014-09-11 00:00:00.0.
PMID: 25079317
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Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.
Authors: Hoadley K.A. , Yau C. , Wolf D.M. , Cherniack A.D. , Tamborero D. , Ng S. , Leiserson M.D. , Niu B. , McLellan M.D. , Uzunangelov V. , et al. .
Source: Cell, 2014-08-14 00:00:00.0; 158(4), p. 929-44.
EPub date: 2014-08-14 00:00:00.0.
PMID: 25109877
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Expanding the computational toolbox for mining cancer genomes.
Authors: Ding L. , Wendl M.C. , McMichael J.F. , Raphael B.J. .
Source: Nature Reviews. Genetics, 2014 Aug; 15(8), p. 556-70.
PMID: 25001846
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SciClone: inferring clonal architecture and tracking the spatial and temporal patterns of tumor evolution.
Authors: Miller C.A. , White B.S. , Dees N.D. , Griffith M. , Welch J.S. , Griffith O.L. , Vij R. , Tomasson M.H. , Graubert T.A. , Walter M.J. , et al. .
Source: Plos Computational Biology, 2014 Aug; 10(8), p. e1003665.
PMID: 25102416
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MSIsensor: microsatellite instability detection using paired tumor-normal sequence data.
Authors: Niu B. , Ye K. , Zhang Q. , Lu C. , Xie M. , McLellan M.D. , Wendl M.C. , Ding L. .
Source: Bioinformatics (oxford, England), 2014-04-01 00:00:00.0; 30(7), p. 1015-6.
EPub date: 2014-04-01 00:00:00.0.
PMID: 24371154
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TIGRA: a targeted iterative graph routing assembler for breakpoint assembly.
Authors: Chen K. , Chen L. , Fan X. , Wallis J. , Ding L. , Weinstock G. .
Source: Genome Research, 2014 Feb; 24(2), p. 310-7.
PMID: 24307552
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High frequency strand slippage mutations in CTCF in MSI-positive endometrial cancers.
Authors: Zighelboim I. , Mutch D.G. , Knapp A. , Ding L. , Xie M. , Cohn D.E. , Goodfellow P.J. .
Source: Human Mutation, 2014 Jan; 35(1), p. 63-5.
PMID: 24130125
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Integrated analysis of germline and somatic variants in ovarian cancer.
Authors: Kanchi K.L. , Johnson K.J. , Lu C. , McLellan M.D. , Leiserson M.D. , Wendl M.C. , Zhang Q. , Koboldt D.C. , Xie M. , Kandoth C. , et al. .
Source: Nature Communications, 2014; 5, p. 3156.
PMID: 24448499
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Advances for studying clonal evolution in cancer.
Authors: Ding L. , Raphael B.J. , Chen F. , Wendl M.C. .
Source: Cancer Letters, 2013-11-01 00:00:00.0; 340(2), p. 212-9.
EPub date: 2013-11-01 00:00:00.0.
PMID: 23353056
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Mutational landscape and significance across 12 major cancer types.
Authors: Kandoth C. , McLellan M.D. , Vandin F. , Ye K. , Niu B. , Lu C. , Xie M. , Zhang Q. , McMichael J.F. , Wyczalkowski M.A. , et al. .
Source: Nature, 2013-10-17 00:00:00.0; 502(7471), p. 333-9.
PMID: 24132290
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Differences that matter in cancer genomics.
Authors: Ding L. , Wendl M.C. .
Source: Nature Biotechnology, 2013 Oct; 31(10), p. 892-3.
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BreakTrans: uncovering the genomic architecture of gene fusions.
Authors: Chen K. , Navin N.E. , Wang Y. , Schmidt H.K. , Wallis J.W. , Niu B. , Fan X. , Zhao H. , McLellan M.D. , Hoadley K.A. , et al. .
Source: Genome Biology, 2013-08-23 00:00:00.0; 14(8), p. R87.
EPub date: 2013-08-23 00:00:00.0.
PMID: 23972288
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Computational approaches to identify functional genetic variants in cancer genomes.
Authors: Gonzalez-Perez A. , Mustonen V. , Reva B. , Ritchie G.R. , Creixell P. , Karchin R. , Vazquez M. , Fink J.L. , Kassahn K.S. , Pearson J.V. , et al. .
Source: Nature Methods, 2013 Aug; 10(8), p. 723-9.
PMID: 23900255
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Integrated genomic characterization of endometrial carcinoma.
Authors: Cancer Genome Atlas Research Network , Kandoth C. , Schultz N. , Cherniack A.D. , Akbani R. , Liu Y. , Shen H. , Robertson A.G. , Pashtan I. , Shen R. , et al. .
Source: Nature, 2013-05-02 00:00:00.0; 497(7447), p. 67-73.
PMID: 23636398
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Retrotransposition of gene transcripts leads to structural variation in mammalian genomes.
Authors: Ewing A.D. , Ballinger T.J. , Earl D. , Broad Institute Genome Sequencing and Analysis Program and Platform , Harris C.C. , Ding L. , Wilson R.K. , Haussler D. .
Source: Genome Biology, 2013-03-13 00:00:00.0; 14(3), p. R22.
EPub date: 2013-03-13 00:00:00.0.
PMID: 23497673
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Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma.
Authors: Gutmann D.H. , McLellan M.D. , Hussain I. , Wallis J.W. , Fulton L.L. , Fulton R.S. , Magrini V. , Demeter R. , Wylie T. , Kandoth C. , et al. .
Source: Genome Research, 2013 Mar; 23(3), p. 431-9.
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