Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations

Abstract

Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies. Homologous recombination deficiency (HRD) levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole-genome sequencing (WGS; n = 311) and whole-exome sequencing (WES) data (n = 498) of both primary and metastatic prostate adenocarcinomas to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Known BRCA-deficient samples showed all previously described HRD-associated mutational signatures in the WGS data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from WES data. These findings may expand the number of cases likely to respond to PARP inhibitor treatment. On the basis of the HR-associated mutational signatures, 5% to 8% of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).