European Urology Open Science · Published 2026-07-27 · DOI 10.1016/j.euros.2026.07.002
Javier Galego-Carro, Marta Santamariña, Ana Blanco-Pérez, Miguel E. Aguado-Barrera, Jorge Amigo, Olivia Fuentes-Ríos, Carla Coedo-Costa, Patricia Calvo-Crespo, Paula Peleteiro-Higuero, Ana María Carballo-Castro, Begoña Taboada-Valladares, Antonio Gómez-Caamaño, Ana Vega
Background: Pathogenic and likely pathogenic (P/LP) germline variants in cancer susceptibility genes (CSGs) are detected in 5–10% of patients with prostate cancer, but their clinical impact in high-risk disease remains unclear. Objective: This study aimed to assess the prevalence of P/LP variants in CSGs among patients with high-risk prostate cancer and their association with oncologic outcomes in patients treated with radiotherapy. Methods: We conducted a retrospective study of 600 men with high-risk prostate cancer. Germline DNA was analyzed using a 19-gene panel, and gene-level variant prevalence was compared with non-cancer control cohorts using Fisher’s exact test. Time-to-event analyses were performed in the 390 patients treated with radiotherapy as primary curative intent. The primary endpoint was overall survival (OS), assessed by Kaplan-Meier and multivariable Cox regression. Secondary endpoints included biochemical recurrence, distant metastasis, prostate cancer–specific mortality (PCSM), and second primary malignancies, analyzed using cumulative incidence functions and Fine-Gray competing-risk models. Key findings and limitations: P/LP variants were identified in 8.0% of patients (n = 48). CHEK2, ATM, and BRCA2 variants were significantly enriched in patients compared with non-cancer control cohorts. BRCA1/BRCA2 carriers had worse OS (10-yr OS rate: 19% vs 57%; p = 0.021) and higher cumulative incidence of biochemical recurrence events (10-yr cumulative incidence: 57% vs 28%; p = 0.048), distant metastases (57% vs 18%; p = 0.004) and PCSM (33% vs 4.3%; p = 0.001) compared with non-carriers. CHEK2 carriers showed heterogeneous family cancer histories and a higher incidence of second primary malignancies (47% vs 15%; p = 0.003). ATM carriers showed no metastatic progression or PCSM during follow-up. Limitations include the single-institution design and small gene-specific subgroups. Conclusions and clinical implications: Germline P/LP variants are prevalent in high-risk prostate cancer and define gene-specific subgroups with distinct oncologic outcomes, supporting the role of germline genetic testing in risk stratification and treatment decision-making.
Abstract from DOAJ. Public domain (CC0 1.0).
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Galego-Carro, J., Santamariña, M., Blanco-Pérez, A., et al. (2026). Clinical Impact of Germline Pathogenic Variants in High-risk Prostate Cancer Treated with Radiotherapy. European Urology Open Science. https://doi.org/10.1016/j.euros.2026.07.002