Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep 2018 Apr 03;23(1):239-254.e6
Date
04/05/2018Pubmed ID
29617664Pubmed Central ID
PMC5961503DOI
10.1016/j.celrep.2018.03.076Scopus ID
2-s2.0-85044676615 (requires institutional sign-in at Scopus site) 654 CitationsAbstract
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.
Author List
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, Cancer Genome Atlas Research Network, Monnat RJ Jr, Xiao Y, Wang CAuthor
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cell Line, TumorDNA Damage
Gene Silencing
Genome, Human
Humans
Loss of Heterozygosity
Machine Learning
Mutation
Neoplasms
Recombinational DNA Repair
Tumor Suppressor Proteins