To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis of 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline whole exome or genome sequencing data, and one cohort with imputed array data. At the gene level, our case-control collapsing analysis confirms associations between rare damaging variants in four genes and increased prostate cancer risk: SAMHD1, BRCA2 and ATM at the study-wide significance level (P < 1×10-8), and CHEK2 at the suggestive threshold (P < 2.6×10-6). Our case-only analysis, reveals that rare damaging variants in AOX1 are associated with more aggressive disease (OR = 2.60 [1.75-3.83], P = 1.35×10-6), as well as confirming the role of BRCA2 in determining disease severity. At the single-variant level, our study reveals that a rare missense variant in TERT is associated with substantially reduced prostate cancer risk (OR = 0.13 [0.07-0.25], P = 4.67×10-10), and confirms rare non-synonymous variants in a further three genes associated with reduced risk (ANO7, SPDL1, AR) and in three with increased risk (HOXB13, CHEK2, BIK). Altogether, this work provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity, with potential implications for clinical risk prediction and therapeutic strategies.
Nature communications. 2025 Feb 19*** epublish ***
Jonathan Mitchell, Niedzica Camacho, Patrick Shea, Konrad H Stopsack, Vijai Joseph, Oliver S Burren, Ryan S Dhindsa, Abhishek Nag, Jacob E Berchuck, Amanda O'Neill, Ali Abbasi, Anthony W Zoghbi, Jesus Alegre-Díaz, Pablo Kuri-Morales, Jaime Berumen, Roberto Tapia-Conyer, Jonathan Emberson, Jason M Torres, Rory Collins, Quanli Wang, David Goldstein, Athena Matakidou, Carolina Haefliger, Lauren Anderson-Dring, Ruth March, Vaidehi Jobanputra, Brian Dougherty, Keren Carss, Slavé Petrovski, Philip W Kantoff, Kenneth Offit, Lorelei A Mucci, Mark Pomerantz, Margarete A Fabre
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. ., Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Institute for Genomic Medicine, Columbia University, New York, NY, USA., Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, NY, USA., Dana-Farber Cancer Institute, Boston, MA, USA., Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Faculty of Medicine, National Autonomous University of Mexico, Copilco Universidad, Coyoacán, Ciudad de México, Mexico., Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK., Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA., Precision Medicine and Biosamples, R&D Oncology, AstraZeneca, Dublin, Ireland., Oncology R&D, AstraZeneca, Waltham, MA, USA., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. .