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Rare germline variants in ATM predispose to prostate cancer: A PRACTICAL Consortium study

Karlsson, Q, Brook, MN, Dadaev, T, Wakerell, S, Saunders, EJ, Muir, K, Neal, DE, Giles, GG, MacInnis, RJ, Thibodeau, SN, McDonnell, SK, Cannon-Albright, L, Teixeira, MR, Paulo, P, Cardoso, M, Huff, C, Li, D, Yao, Y, Scheet, P, Permuth, JB, Stanford, JL, Dai, JY, Ostrander, EA, Cussenot, O, Cancel-Tassin, G, Hoegel, J, Herkommer, K, Schleutker, J, Tammela, TLJ, Rathinakannan, V, Sipeky, C, Wiklund, F, Gronberg, H, Aly, M, Isaacs, WB, Dickinson, JL ORCID: 0000-0003-4621-1703, Fitzgerald, LM ORCID: 0000-0002-6882-2698, Chua, MLK, Nguyen-Dumont, T, Schaid, DJ, Southey, MC, Eeles, RA and Kote-Jarai, Z 2021 , 'Rare germline variants in ATM predispose to prostate cancer: A PRACTICAL Consortium study' , European Urology Oncology , doi: 10.1016/j.euo.2020.12.001.

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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 (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: Article
Authors/Creators: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
Keywords: ATM gene mutations, genetic predisposition, prostate cancer, targeted screening and therapy
Journal or Publication Title: European Urology Oncology
Publisher: Elsevier B.V.
ISSN: 2588-9311
DOI / ID Number: 10.1016/j.euo.2020.12.001
Copyright Information:

Copyright 2020 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology

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