TY - JOUR
T1 - Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas
AU - The Cancer Genome Atlas Research Network
AU - Knijnenburg, Theo A.
AU - Wang, Linghua
AU - Zimmermann, Michael T.
AU - Chambwe, Nyasha
AU - Gao, Galen F.
AU - Cherniack, Andrew D.
AU - Liu, Yuexin
AU - Akbani, Rehan
AU - Weinstein, John N.
AU - Li, Lei
AU - Mills, Gordon B
AU - Zhang, Wei
AU - Broom, Bradley M.
AU - Ju, Zhenlin
AU - Kanchi, Rupa Sridevi
AU - Korkut, Anil
AU - Li, Jun
AU - Liang, Han
AU - Ling, Shiyun
AU - Liu, Wenbin
AU - Lu, Yiling
AU - Uppore Kukkillaya, Arvind Rao
AU - Zhang, Jiexin
AU - Liu, Xiuping
AU - Carvalho, André L.
AU - Fregnani, José Humberto T. G.
AU - Reis, Rui M. V.
AU - Scapulatempo, Cristovam Neto
AU - Ajani, Jaffer A.
AU - Behrens, Carmen
AU - Bondaruk, Jolanta
AU - Broaddus, Russell
AU - Czerniak, Bogdan
AU - Esmaeli, Bita
AU - Fujimoto, Junya
AU - Gershenwald, Jeffrey
AU - Guo, Charles
AU - Lazar, Alexander J.
AU - Logothetis, Christopher
AU - Meric-Bernstam, Funda
AU - Moran, Cesar
AU - Ramondetta, Lois
AU - Rice, David
AU - Sood, Anil
AU - Tamboli, Pheroze
AU - Thompson, Timothy
AU - Troncoso, Patricia
AU - Tsao, Anne
AU - Wistuba, Ignacio
AU - von Deimling, Andreas
N1 - Publisher Copyright:
© 2018 The Author(s)
PY - 2018/4/3
Y1 - 2018/4/3
N2 - 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. Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores.
AB - 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. Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores.
KW - DNA damage footprints
KW - DNA damage repair
KW - The Cancer Genome Atlas PanCanAtlas project
KW - epigenetic silencing
KW - integrative statistical analysis
KW - mutational signatures
KW - protein structure analysis
KW - somatic copy-number alterations
KW - somatic mutations
UR - http://www.scopus.com/inward/record.url?scp=85044676615&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044676615&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2018.03.076
DO - 10.1016/j.celrep.2018.03.076
M3 - Article
C2 - 29617664
AN - SCOPUS:85044676615
SN - 2211-1247
VL - 23
SP - 239-254.e6
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -