| Title: | Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases |
| Journal: | Nature Communications |
| Published: | 19 Feb 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39971927/ |
| DOI: | https://doi.org/10.1038/s41467-025-56944-1 |
Publication 15310
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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.</p>
12 Keywords
- Ataxia Telangiectasia Mutated Proteins
- BRCA2 Protein
- Case-Control Studies
- Checkpoint Kinase 2
- Exome Sequencing
- Genetic Predisposition to Disease
- Germ-Line Mutation
- Humans
- Male
- Mutation, Missense
- Prostatic Neoplasms
- Telomerase
34 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
Enabling scientific discoveries that improve human health