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

Grazi GL

Research output: Contribution to journalArticlepeer-review

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 approximately 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.
Original languageEnglish
Pages (from-to)239-254.e6
JournalCell Reports
Volume23
Issue number1
DOIs
Publication statusPublished - Apr 3 2018
Externally publishedYes

Keywords

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

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