Journal Article

Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases

Matakidou, Athena, Pomerantz, Mark, Petrovski, Slavé, Mitchell, Jonathan, Kantoff, Philip W., Offit, Kenneth, Burren, Oliver S., Emberson, Jonathan, Anderson-Dring, Lauren, Berumen, Jaime, Shea, Patrick, Stopsack, Konrad H., Dougherty, Brian, Nag, Abhishek, Torres, Jason M., Zoghbi, Anthony W., Goldstein, David, March, Ruth, O’Neill, Amanda, Carss, Keren, Berchuck, Jacob E., Camacho, Niedzica, Dhindsa, Ryan S., Kuri-Morales, Pablo, Haefliger, Carolina, Alegre-Díaz, Jesus, Wang, Quanli, Mucci, Lorelei A., Tapia-Conyer, Roberto, Abbasi, Ali, Joseph, Vijai, Collins, Rory, Jobanputra, Vaidehi, Fabre, Margarete A.

2025

Overview

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. By bringing together whole exome and genome sequencing data from five cohorts, the authors assess the contribution of rare germline variants to prostate cancer risk and severity, further validating previously reported genes, and implicating a role for genes not previously reported. Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 45/43 / 631/208/457 / 631/208/68 / 692/4028/67/589/466 / Ataxia Telangiectasia Mutated Proteins - genetics / BRCA2 protein / BRCA2 Protein - genetics / Breast cancer / Case-Control Studies / Checkpoint Kinase 2 - genetics / Data analysis / Gene sequencing / Genes / Genetic analysis / Genetic diversity / Genetic Predisposition to Disease / Genetic variance / Genomes / Genomic analysis / Germ-Line Mutation / Health risks / Humanities and Social Sciences / Humans / Male / Meta-analysis / Middle Aged / multidisciplinary / Peer review / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Rare diseases / Risk Factors / Risk management / Science / Science (multidisciplinary) / Whole genome sequencing