Karlsson, Q and Brook, MN and Dadaev, T and Wakerell, S and Saunders, EJ and Muir, K and Neal, DE and Giles, GG and MacInnis, RJ and Thibodeau, SN and McDonnell, SK and Cannon-Albright, L and Teixeira, MR and Paulo, P and Cardoso, M and Huff, C and Li, D and Yao, Y and Scheet, P and Permuth, JB and Stanford, JL and Dai, JY and Ostrander, EA and Cussenot, O and Cancel-Tassin, G and Hoegel, J and Herkommer, K and Schleutker, J and Tammela, TLJ and Rathinakannan, V and Sipeky, C and Wiklund, F and Gronberg, H and Aly, M and Isaacs, WB and Dickinson, JL and Fitzgerald, LM and Chua, MLK and Nguyen-Dumont, T and Schaid, DJ and Southey, MC and Eeles, RA and Kote-Jarai, Z, PRACTICAL Consortium, Rare germline variants in ATM predispose to prostate cancer: A PRACTICAL Consortium study, European Urology Oncology ISSN 2588-9311 (2021) [Refereed Article]
Copyright 2020 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology
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.
|Item Type:||Refereed Article|
|Keywords:||ATM gene mutations, genetic predisposition, prostate cancer, targeted screening and therapy|
|Research Division:||Biomedical and Clinical Sciences|
|Research Group:||Oncology and carcinogenesis|
|Research Field:||Cancer genetics|
|Objective Group:||Clinical health|
|Objective Field:||Treatment of human diseases and conditions|
|UTAS Author:||Dickinson, JL (Professor Joanne Dickinson)|
|UTAS Author:||Fitzgerald, LM (Dr Liesel Fitzgerald)|
|Web of Science® Times Cited:||17|
|Deposited By:||Menzies Institute for Medical Research|
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