Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.
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Authors
Knijnenburg, Theo A
Wang, Linghua
Zimmermann, Michael T
Chambwe, Nyasha
Gao, Galen F
Cherniack, Andrew D
Fan, Huihui
Shen, Hui
Way, Gregory P
Greene, Casey S
Liu, Yuexin
Akbani, Rehan
Feng, Bin
Donehower, Lawrence A
Miller, Chase
Shen, Yang
Karimi, Mostafa
Chen, Haoran
Kim, Pora
Jia, Peilin
Shinbrot, Eve
Zhang, Shaojun
Liu, Jianfang
Hu, Hai
Bailey, Matthew H
Yau, Christina
Wolf, Denise
Zhao, Zhongming
Weinstein, John N
Li, Lei
Ding, Li
Mills, Gordon B
Laird, Peter W
Wheeler, David A
Shmulevich, Ilya
Cancer Genome Atlas Research Network
Monnat, Raymond J
Xiao, Yonghong
Wang, Chen
Publication Date
2018-04-03Journal Title
Cell Rep
ISSN
2211-1247
Publisher
Elsevier BV
Volume
23
Issue
1
Pages
239-254.e6
Language
eng
Type
Article
Physical Medium
Print
Metadata
Show full item recordCitation
Knijnenburg, T. A., Wang, L., Zimmermann, M. T., Chambwe, N., Gao, G. F., Cherniack, A. D., Fan, H., et al. (2018). Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.. Cell Rep, 23 (1), 239-254.e6. https://doi.org/10.1016/j.celrep.2018.03.076
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.
Keywords
Cancer Genome Atlas Research Network
Identifiers
External DOI: https://doi.org/10.1016/j.celrep.2018.03.076
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280458
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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