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 (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7).
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.
European urology oncology. 2021 Jan 09 [Epub ahead of print]
Questa Karlsson, Mark N Brook, Tokhir Dadaev, Sarah Wakerell, Edward J Saunders, Kenneth Muir, David E Neal, Graham G Giles, Robert J MacInnis, Stephen N Thibodeau, Shannon K McDonnell, Lisa Cannon-Albright, Manuel R Teixeira, Paula Paulo, Marta Cardoso, Chad Huff, Donghui Li, Yu Yao, Paul Scheet, Jennifer B Permuth, Janet L Stanford, James Y Dai, Elaine A Ostrander, Olivier Cussenot, Géraldine Cancel-Tassin, Josef Hoegel, Kathleen Herkommer, Johanna Schleutker, Teuvo L J Tammela, Venkat Rathinakannan, Csilla Sipeky, Fredrik Wiklund, Henrik Grönberg, Markus Aly, William B Isaacs, Jo L Dickinson, Liesel M FitzGerald, Melvin L K Chua, Tu Nguyen-Dumont, PRACTICAL Consortium , Daniel J Schaid, Melissa C Southey, Rosalind A Eeles, Zsofia Kote-Jarai
Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK., Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, UK; Warwick Medical School, University of Warwick, Coventry, UK., Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK; Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK; Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK., Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia., Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA., Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; George E Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA., Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal; Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal; Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal., Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal., Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Departments of Cancer Epidemiology and Gastrointestinal Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA., Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA., GRC n°, AP-HP, Tenon Hospital, Sorbonne Universite, Paris, France; CeRePP, Tenon Hospital, Paris, France., Institute for Human Genetics, University Hospital Ulm, Ulm, Germany., Department of Urology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany., Institute of Biomedicine, University of Turku, Turku, Finland; Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, Turku, Finland., Department of Urology, Tampere University Hospital, Tampere, Finland; Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland., Institute of Biomedicine, University of Turku, Turku, Finland., Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden., Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital, Solna, Stockholm, Sweden; Department of Urology, Karolinska University Hospital, Solna, Stockholm., James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA., University of Tasmania, Menzies Institute for Medical Research, Hobart, Tasmania, Australia., Divisions of Radiation Oncology and Medical Sciences, National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, Singapore., Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Department of Clinical Pathology, The Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia., Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Department of Clinical Pathology, The Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia., Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK., Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK. Electronic address: .