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

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 (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 23

Pages Range: 239-254.e6

Journal Issue: 1

DOI: 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.

Involved external institutions

TESARO Inc United States (USA) (US) Houston Texas Medical Center United States (USA) (US) Institute for Systems Biology United States (USA) (US) University of Texas MD Anderson Cancer Center United States (USA) (US) Medical College of Wisconsin (MCW) United States (USA) (US) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Texas A&M University United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Chan Soon-Shiong Medical Center at Windber United States (USA) (US) Washington University United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) Van Andel Institute United States (USA) (US) University of Washington United States (USA) (US) University of Pennsylvania United States (USA) (US) Mayo Clinic United States (USA) (US)

How to cite

APA:

Knijnenburg, T.A., Wang, L., Zimmermann, M.T., Chambwe, N., Gao, G.F., Cherniack, A.D.,... Wang, C. (2018). Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Reports, 23(1), 239-254.e6. https://doi.org/10.1016/j.celrep.2018.03.076

MLA:

Knijnenburg, Theo A., et al. "Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas." Cell Reports 23.1 (2018): 239-254.e6.

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