Prevalence of germline variants of uncertain significance in DNA repair genes and their potential impact on prostate cancer outcomes following radical prostatectomy.

421 Background: Pathogenic variants (PVs) in DNA repair genes (DRG) are linked to a higher risk of aggressive prostate cancer (PCa). Understanding and managing variants of uncertain significance (VUS), however, remains a challenge. This study investigates the prevalence of germline VUS in PCa patients and their potential link to prognosis following robot-assisted radical prostatectomy (RARP), aiming to enhance clinical management and risk stratification. Methods: This is part of an ongoing PCa screening project in the Italian population aimed at identifying men with a genetic predisposition (AIRC - Fondazione AIRC per la Ricerca sul Cancro, IG 2020 ID 25027). Germline DRG variants were identified in men with high-risk PCa or those aged <50 scheduled for RARP. After informed consent, blood samples were collected, and data on age, stage, PSA, ISUP grade, and family history were recorded. Genetic analysis used a multigene panel, classifying VUS and PVs per ACMG/AMP and IARC guidelines. Primary outcome: VUS prevalence; secondary: correlations between VUS and pathological status, biochemical recurrence (BCR), and need for adjuvant therapy. Results: A total of 138 men who underwent RARP were enrolled. The median age was 64 years (IQR 57–68). ISUP grade was 1–2 in 54.0% of patients and 3–5 in 46.0%. Family history of PCa was present in 55%. Median PSA was 7.5 ng/mL (IQR 3.3–9.4). DRG variants were identified in 41 men (29.7%), of whom 34 (82.9%) had VUS and 7 (17.1%) had PVs (3 BRCA2, 1 BRCA1, 2 PALB2, 1 CHEK2). VUS carriers were younger at diagnosis (median 62 vs. 64 years). 25.8% of VUS carriers were node-positive, compared to 13.5% of those with negative DRG (p > 0.05). BCR occurred in 24% of VUS patients vs. 18% of those without DRG variants at nearly 2.5 years of follow-up, but this difference was not statistically significant. No significant differences in ISUP grade or positive margin rates were observed. Conclusions: VUS germline mutations are common in PCa patients undergoing RARP. These mutations appear associated with worse outcomes. Study limitations include a single-center cohort, small sample size, and a predominantly European ancestry population.