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

TitleGenomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.
Publication TypeJournal Article
Year of Publication2018
AuthorsKnijnenburg, 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
Corporate Authors
JournalCell Rep
Volume23
Issue1
Pagination239-254.e6
Date Published2018 Apr 03
ISSN2211-1247
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.

DOI10.1016/j.celrep.2018.03.076
Alternate JournalCell Rep
PubMed ID29617664
PubMed Central IDPMC5961503
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
U24 CA143882 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
U24 CA143835 / CA / NCI NIH HHS / United States
P01 CA077852 / CA / NCI NIH HHS / United States
U24 CA143866 / CA / NCI NIH HHS / United States
U24 CA210950 / CA / NCI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
U24 CA143799 / CA / NCI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01 CA190635 / CA / NCI NIH HHS / United States
U24 CA144025 / CA / NCI NIH HHS / United States
R35 GM124952 / GM / NIGMS NIH HHS / United States
U24 CA143840 / CA / NCI NIH HHS / United States
U24 CA143843 / CA / NCI NIH HHS / United States
R01 LM012806 / LM / NLM NIH HHS / United States
U24 CA143858 / CA / NCI NIH HHS / United States
U24 CA143848 / CA / NCI NIH HHS / United States
U24 CA210957 / CA / NCI NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
U24 CA210949 / CA / NCI NIH HHS / United States
U24 CA143883 / CA / NCI NIH HHS / United States
U01 CA217883 / CA / NCI NIH HHS / United States
T32 HG000046 / HG / NHGRI NIH HHS / United States
U24 CA143867 / CA / NCI NIH HHS / United States
P50 CA136393 / CA / NCI NIH HHS / United States
R50 CA221675 / CA / NCI NIH HHS / United States
P01 CA193124 / CA / NCI NIH HHS / United States
U24 CA210990 / CA / NCI NIH HHS / United States