How to cite: Helfand, BT. “Newly Identified Germline Mutations Associated with Prostate Cancer Risk and Aggressiveness.” September 15, 2025. Accessed Nov 2025. 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.
ABOUT THE AUTHOR
Brian T. Helfand, MD, PhD, is Chief of the Division of Urology and the Ronald L. Chez Family and Richard Melman Family Endowed Chair at NorthShore University HealthSystem. He is Director of the Personalized Prostate Program and Director of Clinical Research in the Program for Personalized Cancer Care (PPCC). He is also an active surgical scientist who is involved in the care of patients with prostate cancer. His clinical care and research is focused on the implementation of genetic tests and biomarker studies for prostate cancer.
Dr. Helfand completed his undergraduate degree at Emory University. He received his medical training and PhD in Cell and Molecular Biology and Genetics from Northwestern University. He is a fellowship-trained urologic oncologist who has focused his research career on prostate cancer. He was recruited in 2011 from Northwestern University’s Feinberg School of Medicine, where he was faculty in the Department of Urology. Dr. Helfand is an internationally-known urologist and genomic translational researcher. He has received multiple grants from the NIH and has published over 140 peer-reviewed manuscripts in journals such as Nature Genetics, The Journal of Cell Biology, and Science Translational Medicine.
Dr. Helfand is involved in national and international research collaborations as an active member of the International Consortium for Prostate Cancer Genetics (ICPCG), the Prostate Cancer Specialized Program of Research Excellence (SPORE), the IMPACT) study, and the Lower Urinary Tract Dysfunction Research Network (LURN). His current research goals are focused on germline genetic variations and mutations. He is determined to use this information to assist in personal and informed clinical decision making about prostate cancer screening and treatment for patients and their family members.
