Cell Reports
Volume 23, Issue 1, 3 April 2018, Pages 239-254.e6
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Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

https://doi.org/10.1016/j.celrep.2018.03.076Get rights and content
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Highlights

  • DNA damage repair (DDR) gene alterations are prevalent in many human cancer types

  • Homology-dependent recombination (HR) and direct repair were most frequently altered

  • Loss of DDR function is linked to frequency and types of cancer genomic aberrations

  • Altered HR function can be associated with better or worse outcomes by cancer type

Summary

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.

Keywords

The Cancer Genome Atlas PanCanAtlas project
DNA damage repair
somatic mutations
somatic copy-number alterations
epigenetic silencing
DNA damage footprints
mutational signatures
integrative statistical analysis
protein structure analysis

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25

These authors contributed equally

26

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