Abstract IA003: Advances in using germline genetics to inform prostate cancer risk assessment and disease progression

Abstract The decline in prostate cancer screening in recent years has led to a 6% annual increase in patients diagnosed with distant prostate cancer, where the 5-year survival rate is only 38%, demonstrating the urgent need to improve prostate cancer screening practices. Prostate cancer is highly heritable and presents a unique opportunity to implement risk-stratified screening. Accordingly, we have identified many strong genetic risk factors of prostate cancer and developed a polygenic risk score (PRS) that is highly predictive of prostate cancer risk across diverse populations, which could inform the decision to initiate screening, along with the optimal age and frequency of screening. Several of these genetic factors have implications beyond screening—for instance, among patients diagnosed with low-risk prostate cancer being monitored on active surveillance, the PRS was predictive of risk of upgrading or extreme upgrading (i.e., to grade group 3 or higher) along with a higher percentage of cancerous biopsy cores. In recent work, we demonstrated that it is possible to improve the ability of the PRS to distinguish risk of advanced from indolent prostate cancer. This has launched an effort to characterize the common genetic architecture of aggressive prostate cancer by undertaking a large-scale multi-ancestry genome-wide association study (GWAS) focused on prostate cancer aggressiveness. This work is anticipated to identify new genetic mechanisms contributing to the etiology of lethal prostate cancer while also advancing PRS and clinical models to inform prostate cancer screening and treatment decisions. Citation Format: Burcu F. Darst. Advances in using germline genetics to inform prostate cancer risk assessment and disease progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr IA003.