Newly Identified Germline Mutations Associated with Prostate Cancer Risk and Aggressiveness

How to cite: Helfand, BT. “Newly Identified Germline Mutations Associated with Prostate Cancer Risk and Aggressiveness.” September 15, 2025. Accessed Apr 2026. https://grandroundsinurology.com/newly-identified-germline-mutations-associated-with-prostate-cancer-risk-and-aggressiveness/

Brian T. Helfand, MD, PhD, Chief, Division of Urology, NorthShore University HealthSystem, Evanston, Illinois, explains that prostate cancer is the most heritable of solid tumors, with germline DNA variations playing a central role. He distinguishes monogenic mutations, such as BRCA2, ATM, and HOXB13, from polygenic risk scores based on single-nucleotide polymorphisms (SNPs). Monogenic mutations are rare but impart moderate effect sizes, often influencing prognosis and treatment response. Polygenic risk scores are more common and account for the majority of heritability.

Dr. Helfand shares that family history explains approximately 7 percent of cases, but genetic testing now allows for more precise stratification. Among the National Comprehensive Cancer Network (NCCN) -recommended genes, only BRCA2, ATM, HOXB13, CHEK2, and MSH2 are strongly validated for prostate cancer risk.

Emerging evidence highlights additional mutations. A variant in the KLK3 gene, encoding prostate-specific antigen (PSA), increases the risk of aggressive disease and is more common than BRCA2 mutations. Large cohort studies have identified SAMHD1 and BIK as novel susceptibility genes with potential therapeutic implications through apoptosis and DNA repair pathways. A recurrent frameshift founder mutation in MMS22L among Ashkenazi Jewish men is associated with prostate cancer risk and possible sensitivity to PARP inhibition.

Polygenic risk scores continue to demonstrate clinical utility. The prospective BARCODE1 trial confirmed that men in the top 10 percent of risk had a threefold increase in prostate cancer, independent of PSA, and were more likely to present with higher-grade disease. These tools may inform earlier screening, influence treatment selection, and identify susceptibility to other malignancies.

The Global Summit on Precision Diagnosis and Treatment of Prostate Cancer is a unique multi-disciplinary forum organized to inform the key health care stakeholders about the emerging advances in clinical cases and research and create a consensus-based vision for the future of precision care and educational and research strategy for its realization. The mission of the Summit is to fill the currently existing gap between the key experts of in vivo imaging, the world authorities in the in vitro fluid- and tissue-based molecular diagnostics, including genomics, and thought leaders in the development of novel observation strategies (e.g., active surveillance, or AS) and therapeutic interventions.