Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.
Journal of the National Cancer Institute. 2023 Apr 11 [Epub]
Kathleen E Houlahan, Julie Livingstone, Natalie S Fox, Natalie Kurganovs, Helen Zhu, Jocelyn Sietsma Penington, Chol-Hee Jung, Takafumi N Yamaguchi, Lawrence E Heisler, Richard Jovelin, Anthony J Costello, Bernard J Pope, Amar U Kishan, Niall M Corcoran, Robert G Bristow, Sebastian M Waszak, Joachim Weischenfeldt, Housheng H He, Rayjean J Hung, Christopher M Hovens, Paul C Boutros
Department of Human Genetics, University of California, Los Angeles, CA, USA., Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia., Department of Medical Biophysics, University of Toronto, Toronto, Canada., Bioinformatics Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia., Melbourne Bioinformatics, The University of Melbourne, Parkville, VIC, Australia., Ontario Institute for Cancer Research, Toronto, Canada., Division of Urology, Royal Melbourne Hospital, Parkville, VIC, Australia., Department of Surgery, The University of Melbourne, Parkville, VIC, Australia., Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA., Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo, and Oslo University Hospital, Oslo, Norway., Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark., Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.