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Document type:
Article; Journal Article
Author(s):
Karlsson, Questa; Brook, Mark N; Dadaev, Tokhir; Wakerell, Sarah; Saunders, Edward J; Muir, Kenneth; Neal, David E; Giles, Graham G; MacInnis, Robert J; Thibodeau, Stephen N; McDonnell, Shannon K; Cannon-Albright, Lisa; Teixeira, Manuel R; Paulo, Paula; Cardoso, Marta; Huff, Chad; Li, Donghui; Yao, Yu; Scheet, Paul; Permuth, Jennifer B; Stanford, Janet L; Dai, James Y; Ostrander, Elaine A; Cussenot, Olivier; Cancel-Tassin, Géraldine; Hoegel, Josef; Herkommer, Kathleen; Schleutker, Johanna; Tamme...     »
Title:
Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.
Abstract:
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 (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). 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.
Journal title abbreviation:
Eur Urol Oncol
Year:
2021
Journal volume:
4
Journal issue:
4
Pages contribution:
570-579
Fulltext / DOI:
doi:10.1016/j.euo.2020.12.001
Pubmed ID:
http://view.ncbi.nlm.nih.gov/pubmed/33436325
Print-ISSN:
2588-9311
TUM Institution:
285; Urologische Klinik und Poliklinik
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