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The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor

Brandão A 1 , Paulo P 1 , Maia S 1 , Pinheiro M 1 , Peixoto A 2 , Cardoso M 1 Show all authors , Silva MP 1 , Santos C 2 , Eeles RA 3 , Kote-Jarai Z 3 , Muir K 4 , Ukgpcs Collaborators 5 , Schleutker J 6 , Wang Y 7 , Pashayan N 8 , Batra J 9 , Apcb BioResource 9 , Grönberg H 10 , Neal DE 11 , Nordestgaard BG 12 , Tangen CM 13 , Southey MC 14 , Wolk A 15 , Albanes D 16 , Haiman CA 17 , Travis RC 18 , Stanford JL 19 , Mucci LA 20 , West CML 21 , Nielsen SF 12 , Kibel AS 22 , Cussenot O 23 , Berndt SI 16 , Koutros S 16 , Sørensen KD 24 , Cybulski C 25 , Grindedal EM 26 , Park JY 27 , Ingles SA 28 , Maier C 29 , Hamilton RJ 30 , Rosenstein BS 31 , Vega A 32 , The Impact Study Steering Committee And Collaborators 5 , Kogevinas M 33 , Wiklund F 10 , Penney KL 34 , Brenner H 35 , John EM 36 , Kaneva R 37 , Logothetis CJ 38 , Neuhausen SL 39 , Ruyck K 40 , Razack A 41 , Newcomb LF 19 , Canary Pass Investigators 19 , Lessel D 42 , Usmani N 43 , Claessens F 44 , Gago-Dominguez M 45 , Townsend PA 46 , Roobol MJ 47 , The Profile Study Steering Committee 48 , The Practical Consortium , Teixeira MR 1

Affiliations 

  • 1 Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
  • 2 Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
  • 3 The Institute of Cancer Research, London SM2 5NG, UK
  • 4 Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester M13 9PL, UK
  • 5 The Institute of Cancer Research, London SW7 3RP, UK
  • 6 Institute of Biomedicine, University of Turku, FI-20014 Turun Yliopisto, 20050 Turku, Finland
  • 7 Department of Population Science, American Cancer Society, 250 Williams Street, Atlanta, GA 30303, USA
  • 8 Department of Applied Health Research, University College London, London WC1E 7HB, UK
  • 9 Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD 4059, Australia
  • 10 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm, Sweden
  • 11 Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
  • 12 Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
  • 13 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M3-C102, Seattle, WA 98109-1024, USA
  • 14 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia
  • 15 Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
  • 16 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, ML 20892, USA
  • 17 Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90015, USA
  • 18 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK
  • 19 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, DC 98109-1024, USA
  • 20 Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA
  • 21 Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester M13 9PL, UK
  • 22 Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA
  • 23 Sorbonne Universite, GRC n 5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-75020 Paris, France
  • 24 Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200 Aarhus N, Denmark
  • 25 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland
  • 26 Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway
  • 27 Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
  • 28 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90015, USA
  • 29 Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076 Tuebingen, Germany
  • 30 Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada
  • 31 Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Box 1236, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
  • 32 Fundación Pública Galega Medicina Xenómica, 15706 Santiago de Compostela, Spain
  • 33 ISGlobal, 08036 Barcelona, Spain
  • 34 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02184, USA
  • 35 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • 36 Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, USA
  • 37 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria
  • 38 Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
  • 39 Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
  • 40 Faculty of Medicine and Health Sciences, Basic Medical Sciences, Ghent University, Proeftuinstraat 86, 9000 Gent, Belgium
  • 41 Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
  • 42 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
  • 43 Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
  • 44 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, Campus Gasthuisberg, University of Leuven, Herestraat 49, P.O. Box 901, 3000 Leuven, Belgium
  • 45 Group of Genomic Medicine, Galician Public Foundation of Genomic Medicine, Health Research Institute of Santiago de Compostela (IDIS), Galician Healthcare Service (SERGAS) University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
  • 46 Division of Cancer Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, Health Innovation Manchester, University of Manchester, Manchester M13 9PL, UK
  • 47 Department of Urology, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands
  • 48 Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK
Cancers (Basel), 2020 Nov 04;12(11).
PMID: 33158149 DOI: 10.3390/cancers12113254

Abstract

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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