Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.
ATM gene mutations
Genetic predisposition
Prostate cancer
Targeted screening and therapy
Journal
European urology oncology
ISSN: 2588-9311
Titre abrégé: Eur Urol Oncol
Pays: Netherlands
ID NLM: 101724904
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
27
10
2020
revised:
23
11
2020
accepted:
01
12
2020
pubmed:
14
1
2021
medline:
2
2
2022
entrez:
13
1
2021
Statut:
ppublish
Résumé
Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. To precisely estimate the contribution of germline ATM mutations to PrCa risk. We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (p Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
Sections du résumé
BACKGROUND
Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.
OBJECTIVE
To precisely estimate the contribution of germline ATM mutations to PrCa risk.
DESIGN, SETTING, AND PARTICIPANTS
We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated.
RESULTS AND LIMITATIONS
PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (p
CONCLUSIONS
Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families.
PATIENT SUMMARY
In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
Identifiants
pubmed: 33436325
pii: S2588-9311(20)30209-1
doi: 10.1016/j.euo.2020.12.001
pmc: PMC8381233
pii:
doi:
Substances chimiques
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
570-579Subventions
Organisme : NCI NIH HHS
ID : R01 CA196931
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222833
Pays : United States
Organisme : Cancer Research UK
ID : C5047/A17528
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
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