Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

The Cancer Genome Atlas Research Network

Research output: Contribution to journalArticlepeer-review

226 Scopus citations

Abstract

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy. Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores.

Original languageEnglish (US)
Pages (from-to)239-254.e6
JournalCell reports
Volume23
Issue number1
DOIs
StatePublished - Apr 3 2018

Bibliographical note

Funding Information:
This work was supported by the following grants from the NIH : U54 HG003273 , U54 HG003067 , U54 HG003079 , U24 CA143799 , U24 CA143835 , U24 CA143840 , U24 CA143843 , U24 CA143845 , U24 CA143848 , U24 CA143858 , U24 CA143866 , U24 CA143867 , U24 CA143882 , U24 CA143883 , U24 CA144025 , P30 CA016672 , U24 CA210949 , and U24 CA210950 . Investigators were supported in part by P01CA077852 (T.A.K., N.C., I.S., and R.J.M.), U01 CA217883 (T.A.K, N.C., and I.S.), R35GM124952 (Y.S., M.K., and H.C.), GBMF 4552 (C.S.G.), T32 HG000046 (G.P.W.), R01LM012806 (Z.Z., P.K., and P.J.), DOD W81XWH-12-2-0050 , HU0001-16-2-0004 (J.L. and H.H.), W81XWH-16-1-0237 (R.A.), U24 CA210990 (C.Y.), CA190635 and P01CA193124 (L.L.), P50 CA136393 (C.W.), and the Mayo Clinic Center for Individualized Medicine (M.T.Z. and C.W.). We are grateful to Dr. Allison Kudla (Institute for Systems Biology) for her contributions in forming the graphical abstract.

Funding Information:
Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc and is employed by Genospace. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae.

Publisher Copyright:
© 2018 The Author(s)

Keywords

  • DNA damage footprints
  • DNA damage repair
  • The Cancer Genome Atlas PanCanAtlas project
  • epigenetic silencing
  • integrative statistical analysis
  • mutational signatures
  • protein structure analysis
  • somatic copy-number alterations
  • somatic mutations

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