Genomic Determinants of Homologous Recombination Deficiency across Human Cancers

SIMPLE SUMMARY: Tumors with homologous recombination deficiency (HRD) respond to Poly-ADP ribose polymerase inhibitor (PARPi) therapy in breast, ovarian, prostate, and pancreatic cancers. However, in addition to a handful of known pathogenic variants including those affecting BRCA1/2, it remains unclear what other genomic events can cause HRD. Our study systematically examined the germline and somatic genome of over 9000 cancers. We identified alterations associated with HRD, including mutations in ATM and ATR genes; specific deletions in stomach, bladder, and lung cancer; and BRCA-wild type breast, ovarian, and pancreatic cancers. These findings suggest a potentially broader utility for PARPi for cancers harboring a wide range of genomic alterations. ABSTRACT: Germline BRCA1/2 mutations associated with HRD are clinical biomarkers for sensitivity to poly-ADP ribose polymerase inhibitors (PARPi) treatment in breast, ovarian, pancreatic, and prostate cancers. However, it remains unclear whether other mutations may also lead to HRD and PARPi sensitivity across a broader range of cancer types. Our goal was to determine the germline or somatic alterations associated with the HRD phenotype that might therefore confer PARPi sensitivity. Using germline and somatic genomic data from over 9000 tumors representing 32 cancer types, we examined associations between HRD scores and pathogenic germline variants, somatic driver mutations, and copy number deletions in 30 candidate genes involved in homologous recombination. We identified several germline and somatic mutations (e.g., BRCA1/2, PALB2, ATM, and ATR mutations) associated with HRD phenotype in ovarian, breast, pancreatic, stomach, bladder, and lung cancer. The co-occurrence of germline BRCA1 variants and somatic TP53 mutations was significantly associated with increasing HRD in breast cancer. Notably, we also identified multiple somatic copy number deletions associated with HRD. Our study suggests that multiple cancer types include tumor subsets that show HRD phenotype and should be considered in the future clinical studies of PARPi and synthetic lethality strategies exploiting HRD, which can be caused by a large number of genomic alterations.