BRCA1/2 and CHEK2 Pathogenic Variants in Urological Cancers: A Portuguese Single-Center Experience

Background Germline pathogenic variants (gPVs) in BRCA1, BRCA2, and CHEK2 are well‑established cancer predisposition factors of prostate cancer. However, their contribution across the full spectrum of urological cancers remains insufficiently characterized. The primary objective was to describe the spectrum and outcomes of urological cancers in BRCA1/2 and CHEK2 gPV carriers, while secondary objectives were to assess overall survival (OS) and compare age at diagnosis, stage, and survival outcome by gene affected. Methods This is a retrospective descriptive study including patients diagnosed with urological cancers and testing positive for gPVs in BRCA1, BRCA2, or CHEK2, identified at the Hereditary Cancer Risk Clinic of the Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG). Familial and individual files were systematically reviewed to identify individuals with urological malignancies carrying gPVs. Descriptive statistics were used to summarize clinicopathologic characteristics. Survival outcomes were estimated using the Kaplan-Meier method and log-rank test for comparisons between groups, with p<0.05 considered statistically significant. Results A total of 968 BRCA1/2 or CHEK2 families were identified, of which 47 included 50 patients with urological cancer and a gPV in the genes of interest. Among BRCA1/2 carriers, BRCA2 was the most frequently affected gene (37 patients), with the BRCA2 Portuguese founder variant (c.156_157insAlu) identified in 23.1% of cases. Among prostate cancer patients carrying BRCA1/2 gPVs, all individuals with high-grade or metastatic disease carried BRCA2 gPVs. These patients were diagnosed at a younger age than either what is expected from the general population or patients with BRCA1-associated prostate cancer in this study. Also, BRCA2 prostate cancer patients were more frequently diagnosed with other cancers, with male breast cancer being the most frequent (32%). Regarding family history, breast cancer was the most common malignancy observed (71% in BRCA1 and 74% in BRCA2 families), followed by other cases of prostate cancer (42% in BRCA1 vs. 34% in BRCA2). The median OS among prostate cancer patients with advanced disease was 38 months (95% CI: 5.6-70.3), with no statistically significant difference between BRCA1 and BRCA2 carriers (p=0.408). All renal cancer patients with BRCA gPVs were female, had a personal history of breast cancer, and presented clear cell histology. Among urothelial cancer patients, one carried a BRCA1 gPV, and six carried BRCA2 gPVs. Most presented with non-muscle‑invasive bladder cancer (71.4%), except for two BRCA2 carriers who had advanced disease. CHEK2‑associated urological cancers included renal cancer (n=1) and prostate cancer (n=5), all of which showed favorable outcomes. No testicular cancers were identified. Conclusion This study highlights the heterogeneous spectrum of urological cancers associated with BRCA1, BRCA2, and CHEK2 gPVs in a Portuguese cohort, including the role of the Portuguese founder variant. While prostate cancer is the most frequent urological cancer in these families, increasing access to and awareness of genetic testing may better inform future studies about these cancer phenotypes. We reinforce that the systematic assessment of personal and family cancer history in these patients may assist in identifying individuals who could benefit from genetic evaluation and tailored surveillance strategies for carriers and their families.