PURPOSE: PARP inhibitors are approved for use in breast, ovarian, prostate and pancreatic cancer, which are the solid tumor types that most frequently have alterations in key homologous recombination (HR) genes, such as BRCA1/2 However, the frequency of HR deficiency in other solid tumor types, including bladder cancer, is less well characterized.

EXPERIMENTAL DESIGN: Specific DNA aberration profiles (mutational signatures) are induced by homologous recombination deficiency (HRD) and the presence of these "genomic scars" can be used to assess the presence or absence of HR deficiency in a given tumor biopsy even in the absence of an observed alteration of an HR gene. Using whole exome and whole genome data, we measured various HR deficiency-associated mutational signatures in bladder cancer.

RESULTS: We found that a subset of bladder tumors have evidence of HR deficiency. In addition to a small number of tumors with bi-allelic BRCA1/2 events, approximately 10% of bladder tumors had significant evidence of HR deficiency associated mutational signatures. Increased levels of HRD signatures were associated with promoter methylation of RBBP8 which encodes CtIP, a key protein involved in HR.

CONCLUSION: A subset of bladder tumors have genomic features suggestive of HR deficiency and therefore may be more likely to benefit from therapies such as platinum agents and PARP inhibitors that target tumor HR deficiency.