Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2018-04-03
Date Acceptance
2018-03-19
Citation
Cell Reports, 2018, 23 (1), pp.239-254
ISSN
2211-1247
Publisher
Elsevier
Start Page
239
End Page
254
Journal / Book Title
Cell Reports
Volume
23
Issue
1
Copyright Statement
© 2018 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Sponsor
SAIC-F-Frederick, Inc
Leidos Biomedical Research, Inc.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000429092900021&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
TCGA Pilot Program
15Y011ST
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell Biology
REPLICATION FORK STABILITY
MICROSATELLITE INSTABILITY
PROMOTER HYPERMETHYLATION
POLYMERASE-EPSILON
PREDICTS RESPONSE
STRUCTURAL BASIS
MUTANT-CELLS
HUMAN COLON
MUTATIONS
INACTIVATION
Publication Status
Published
Date Publish Online
2018-04-05