TY - JOUR
T1 - Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas
AU - Knijnenburg, Theo A.
AU - Wang, Linghua
AU - Zimmermann, Michael T.
AU - Chambwe, Nyasha
AU - Gao, Galen F.
AU - Cherniack, Andrew D.
AU - Fan, Huihui
AU - Shen, Hui
AU - Way, Gregory P.
AU - Greene, Casey S.
AU - Liu, Yuexin
AU - Akbani, Rehan
AU - Feng, Bin
AU - Donehower, Lawrence A.
AU - Miller, Chase
AU - Shen, Yang
AU - Karimi, Mostafa
AU - Chen, Haoran
AU - Kim, Pora
AU - Jia, Peilin
AU - Shinbrot, Eve
AU - Zhang, Shaojun
AU - Liu, Jianfang
AU - Hu, Hai
AU - Bailey, Matthew H.
AU - Yau, Christina
AU - Wolf, Denise
AU - Zhao, Zhongming
AU - Weinstein, John N.
AU - Li, Lei
AU - Ding, Li
AU - Mills, Gordon B.
AU - Laird, Peter W.
AU - Wheeler, David A.
AU - Shmulevich, Ilya
AU - Caesar-Johnson, Samantha J.
AU - Demchok, John A.
AU - Felau, Ina
AU - Kasapi, Melpomeni
AU - Ferguson, Martin L.
AU - Hutter, Carolyn M.
AU - Sofia, Heidi J.
AU - Tarnuzzer, Roy
AU - Wang, Zhining
AU - Yang, Liming
AU - Zenklusen, Jean C.
AU - Zhang, Jiashan (Julia)
AU - Chudamani, Sudha
AU - Lolla, Laxmi
AU - Mann, Graham
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
U2 - 10.1016/j.celrep.2018.03.076
DO - 10.1016/j.celrep.2018.03.076
M3 - Article
SN - 2211-1247
VL - 23
SP - 239-254.e6
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -