Inherited susceptibility to prostate cancer in Spanish population: who are the players?

Background: Prostate cancer (PCa) is one of the most heritable common malignancies, yet data on germline genetic susceptibility in the Spanish population remain limited and testing indications vary across guidelines. We aimed to characterize germline pathogenic variants (PVs) in Spanish PCa patients and identify predictors of carrier status. Methods: We retrospectively analyzed 360 PCa patients referred for genetic counseling. Multigene panel testing of 13 cancer predisposition genes was performed. PV frequencies were compared with internal pseudo-controls and public population controls. Associations with age at diagnosis, clinical risk group, and family history (FH) were evaluated. Results: Overall, 6.4% of patients carried a germline PV. BRCA2 and ATM were the most frequently mutated genes (1.67% each), showing significant enrichment compared with all control groups. PALB2 and TP53 were also significantly associated with PCa risk. High-risk or metastatic disease, age < 60 years, and FH of hereditary breast/ovarian or Lynch syndrome-spectrum tumors were the best predictors for the presence of PV. Conclusions: Our findings support BRCA2 and ATM as key PCa susceptibility genes and suggest an unexpected major role for PALB2 and TP53 . Genetic testing may be most informative when focused on younger patients with non-low-risk disease and relevant FH.