Detection of Molecular Signatures of Homologous Recombination Deficiency in Bladder Cancer

Purpose: Poly (ADP ribose)-polymerase (PARP) inhibitors arc approved for use in breast, ovarian, prostate, and pancreatic cancers, 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 (HRD) in other solid tumor types, including bladder cancer, is less well characterized. Experimental Design: Specific DNA aberration profiles (mutational signatures) are induced by HRD, and the presence of these "genomic scars" can be used to assess the presence or absence of HRD 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 HRD-associated mutational signatures in bladder cancer. Results: We found that a subset of bladder tumors have evidence of HRD. In addition to a small number of tumors with biallelic BRCA1/2 events, approximately 10% of bladder tumors had significant evidence of HRD-associated mutational signatures. Increased levels of HRD signatures were associated with promoter methylation of RBBP8, which encodes CUP, a key protein involved in HR. Conclusions: A subset of bladder tumors have genomic features suggestive of HRD and therefore may be more likely to benefit from therapies such as platinum agents and PARP inhibitors that target tumor HRD.