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Genomic and molecular landscape of dna damage repair deficiency across the cancer genome atlas

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Title: Genomic and molecular landscape of dna damage repair deficiency across the cancer genome atlas
Authors: Knijnenburg, TA
Wang, L
Zimmermann, MT
Chambwe, N
Gao, GF
Cherniack, AD
Fan, H
Shen, H
Way, GP
Greene, CS
Liu, Y
Akbani, R
Feng, B
Donehower, LA
Miller, C
Shen, Y
Karimi, M
Chen, H
Kim, P
Jia, P
Shinbrot, E
Zhang, S
Liu, J
Hu, H
Bailey, MH
Yau, C
Wolf, D
Zhao, Z
Weinstein, JN
Li, L
Ding, L
Mills, GB
Laird, PW
Wheeler, DA
Shmulevich, I
Monnat, RJ
Xiao, Y
Wang, C
Item 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.
Issue Date: 3-Apr-2018
Date of Acceptance: 19-Mar-2018
URI: http://hdl.handle.net/10044/1/71266
DOI: https://doi.org/10.1016/j.celrep.2018.03.076
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/Funder: SAIC-F-Frederick, Inc
Leidos Biomedical Research, Inc.
Funder's Grant Number: TCGA Pilot Program
15Y011ST
Keywords: 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
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
Cancer Genome Atlas Research Network
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
Online Publication Date: 2018-04-05
Appears in Collections:Department of Surgery and Cancer