BRCA-Mutated Prostatic Adenocarcinoma: A Distinct Clinicopathological Subset With Frequent Cribriform Morphology Associated With Domain-Specific Alterations in Putative Protein Properties

Background: Several studies have demonstrated a worse prognosis in BRCA1 (BRCA1 DNA repair associated)- and BRCA2 (BRCA2 DNA repair associated)-mutated prostatic adenocarcinomas, including shorter disease-free survival, an increased risk of disease progression, and inferior overall survival. This study presents a comparative clinicopathologic analysis of grade-matched BRCA1/2-mutant and wild-type prostatic adenocarcinomas. Materials and Methods: Cases of prostatic adenocarcinoma that underwent broad-panel next-generation sequencing (NGS) and were found to harbor BRCA1 and/or BRCA2 mutations were retrieved from the pathology archives. The control group consisted of age, Gleason grade group, and stage-matched prostatic adenocarcinomas negative for BRCA1 and/or BRCA2 mutations. The hematoxylin and eosin (H&E) slides from both cohorts were retrieved and reviewed. The presence and location of metastasis were also recorded. The NGS data were reviewed, and the reported BRCA1 and BRCA2 variants were analyzed. Statistical analysis was performed using IBM SPSS 26 software for Windows, version 26.0 (IBM Corp., Armonk, NY, USA). Results: Histological review of the two groups showed a similar distribution of intraductal carcinoma, neuroendocrine differentiation, perineural invasion, necrosis, extraprostatic extension, and metastatic disease. Cribriform pattern was present in all BRCA-mutated cases in the study cohort, but was completely absent in the control group (p = 0.022). The BRCA1 variants were identified in three cases (30%) and included one splice-site variant, one frameshift variant, one nonsense variant, and one missense variant. The nonsense mutation was predicted to disrupt molecular recognition features, amidation, calcium binding, catalytic sites, and carboxylation (p < 0.01). In contrast, BRCA2 variants were identified in nine cases, including three cases with BRCA2 loss, one case with a large genomic rearrangement involving introns 16 and 18, three cases with missense variants and two cases with frameshift variants. The two frameshift variants showed similar predicted disruption of protein function with significant impact on protein–protein interaction hotspots, catalytic sites, iron binding, and sulfation (p = 0.01). Conclusion: The current study found that prostatic adenocarcinoma with cribriform morphology may be enriched for BRCA alterations and could be used to prioritize BRCA mutation testing, pending validation in larger cohorts. Mutation Prediction for Loss-of-Function (MutPred-LOF) algorithmic prediction of molecular mechanisms of pathogenicity identified variants that may impact catalytic sites, ion binding, and post-translational chemical modifications in this subgroup of BRCA-mutated prostatic adenocarcinomas; however, further functional studies are required to confirm these findings.