Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases
Abstract
Abstract 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.
Article Details
Authors (34)
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
Jesús 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
New York Genome Center
Brian Dougherty
Keren Carss
Slavé Petrovski
Philip W. Kantoff
Kenneth Offit
Lorelei A. Mucci
Mark Pomerantz
Margarete A. Fabre