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


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.

SUBMITTER: Knijnenburg TA 

PROVIDER: S-EPMC5961503 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Knijnenburg Theo A TA   Wang Linghua L   Zimmermann Michael T MT   Chambwe Nyasha N   Gao Galen F GF   Cherniack Andrew D AD   Fan Huihui H   Shen Hui H   Way Gregory P GP   Greene Casey S CS   Liu Yuexin Y   Akbani Rehan R   Feng Bin B   Donehower Lawrence A LA   Miller Chase C   Shen Yang Y   Karimi Mostafa M   Chen Haoran H   Kim Pora P   Jia Peilin P   Shinbrot Eve E   Zhang Shaojun S   Liu Jianfang J   Hu Hai H   Bailey Matthew H MH   Yau Christina C   Wolf Denise D   Zhao Zhongming Z   Weinstein John N JN   Li Lei L   Ding Li L   Mills Gordon B GB   Laird Peter W PW   Wheeler David A DA   Shmulevich Ilya I   Monnat Raymond J RJ   Xiao Yonghong Y   Wang Chen C  

Cell reports 20180401 1


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 (H  ...[more]

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