Genomic architecture of prostate cancer in BRCA1/2 germline carriers

Background: Inherited pathogenic germline variants (PGVs) in BRCA1 and BRCA2 are significant risk factors for the development of prostate cancer (PCa). Individuals with BRCA2 PGVs have a 3-4-fold increased risk of developing PCa and demonstrate higher Gleason scores, increased nodal metastases, and overall poorer survival. However, the mechanisms by which BRCA1/2 loss promotes PCa development is unknown. In this study we aim to summarize somatic genomic alterations of BRCA1 and BRCA2 carriers with PCa. Methods: Germline carriers of PGV or putative PGV BRCA1/2 variants with PCa were identified in the Veteran Affairs National Precision Oncology Program (VA-NPOP) by either clinical genetic testing or by sequencing of liquid biopsies (VAF > 30%). Controls were patients with no PGV in any cancer risk gene on germline genetic testing. Somatic mutations were identified from tumor tissue or liquid biopsy tests as PCa patients were stratified by hormone sensitive prostate cancer (HSPC) and castration resistant prostate cancer (CRPC) clinical status. Fishers' exact tests were used to compare mutation frequencies in 30 genes, tumor mutational burden (TMB), and microsatellite instability (MSI) scores in BRCA1 or BRCA2 carriers vs. germline negative controls. Results: A total of 85 patients with BRCA1/2 variants were included in the study (n=70 BRCA2 , n=15 BRCA1 ) with 1,124 control patients including 844 and 365 PCa patients who had HSPC and CRPC, respectively. Of the HSPC patients who received a tumor tissue test, BRCA2 carriers had a significantly higher mutation frequency of the PRKCI gene compared to controls (13% (n=16) vs n=1% (n=560), p=0.023, respectively). Of the CRPC patients who received a liquid biopsy test, BRCA2 carriers had a significantly higher mutation frequency of the KDM6A gene compared to controls (13% (n=38) vs 2% (n=318), p=0.005, respectively). Additionally, mutations in the APC gene were found at a higher frequency in BRCA1 carriers (22% (n=9) vs 3% (n=318), p=0.027). There was no significant difference in tumor mutational burden and microsatellite instability measurements between BRCA1 and BRCA2 carriers and controls regardless of the type of somatic test and sensitivity to hormone therapy. Further work is required to understand mechanisms that contribute to these genomic differences, therefore, we have expanded this study to understand transcriptomic differences between BRCA2 carriers (n=30) and non-carriers (n=60) with localized PCa by performing bulk DNA and RNA-sequencing and single cell RNA sequencing of fresh BRCA2 (n=10) prostate tissues and clinically matched control patients (n=20). Conclusions: We report differences in genomic alteration frequencies in PRKCI , KDM6A , and APC between BRCA1 and BRCA2 germline carriers and controls in VA-NPOP. Further work is needed to determine the functional role of genomic and transcriptomic differences in BRCA1/2 carriers and non-carriers.