Cancers (Nov 2020)
The <i>CHEK2</i> Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor
- Andreia Brandão,
- Paula Paulo,
- Sofia Maia,
- Manuela Pinheiro,
- Ana Peixoto,
- Marta Cardoso,
- Maria P. Silva,
- Catarina Santos,
- Rosalind A. Eeles,
- Zsofia Kote-Jarai,
- Kenneth Muir,
- UKGPCS Collaborators,
- Johanna Schleutker,
- Ying Wang,
- Nora Pashayan,
- Jyotsna Batra,
- APCB BioResource,
- Henrik Grönberg,
- David E. Neal,
- Børge G. Nordestgaard,
- Catherine M. Tangen,
- Melissa C. Southey,
- Alicja Wolk,
- Demetrius Albanes,
- Christopher A. Haiman,
- Ruth C. Travis,
- Janet L. Stanford,
- Lorelei A. Mucci,
- Catharine M. L. West,
- Sune F. Nielsen,
- Adam S. Kibel,
- Olivier Cussenot,
- Sonja I. Berndt,
- Stella Koutros,
- Karina Dalsgaard Sørensen,
- Cezary Cybulski,
- Eli Marie Grindedal,
- Jong Y. Park,
- Sue A. Ingles,
- Christiane Maier,
- Robert J. Hamilton,
- Barry S. Rosenstein,
- Ana Vega,
- The IMPACT Study Steering Committee and Collaborators,
- Manolis Kogevinas,
- Fredrik Wiklund,
- Kathryn L. Penney,
- Hermann Brenner,
- Esther M. John,
- Radka Kaneva,
- Christopher J. Logothetis,
- Susan L. Neuhausen,
- Kim De Ruyck,
- Azad Razack,
- Lisa F. Newcomb,
- Canary PASS Investigators,
- Davor Lessel,
- Nawaid Usmani,
- Frank Claessens,
- Manuela Gago-Dominguez,
- Paul A. Townsend,
- Monique J. Roobol,
- The Profile Study Steering Committee,
- The PRACTICAL Consortium,
- Manuel R. Teixeira
Affiliations
- Andreia Brandão
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- Paula Paulo
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- Sofia Maia
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- Manuela Pinheiro
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- Ana Peixoto
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- Marta Cardoso
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- Maria P. Silva
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- Catarina Santos
- Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- Rosalind A. Eeles
- The Institute of Cancer Research, London SM2 5NG, UK
- Zsofia Kote-Jarai
- The Institute of Cancer Research, London SM2 5NG, UK
- Kenneth Muir
- Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester M13 9PL, UK
- UKGPCS Collaborators
- The Institute of Cancer Research, London SW7 3RP, UK
- Johanna Schleutker
- Institute of Biomedicine, University of Turku, FI-20014 Turun Yliopisto, 20050 Turku, Finland
- Ying Wang
- Department of Population Science, American Cancer Society, 250 Williams Street, Atlanta, GA 30303, USA
- Nora Pashayan
- Department of Applied Health Research, University College London, London WC1E 7HB, UK
- Jyotsna Batra
- 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
- APCB BioResource
- 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
- Henrik Grönberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm, Sweden
- David E. Neal
- Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
- Børge G. Nordestgaard
- Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Catherine M. Tangen
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M3-C102, Seattle, WA 98109-1024, USA
- Melissa C. Southey
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia
- Alicja Wolk
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
- Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, ML 20892, USA
- Christopher A. Haiman
- 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
- Ruth C. Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK
- Janet L. Stanford
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, DC 98109-1024, USA
- Lorelei A. Mucci
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA
- Catharine M. L. West
- 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
- Sune F. Nielsen
- Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- Adam S. Kibel
- Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA
- Olivier Cussenot
- Sorbonne Universite, GRC n 5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-75020 Paris, France
- Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, ML 20892, USA
- Stella Koutros
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, ML 20892, USA
- Karina Dalsgaard Sørensen
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200 Aarhus N, Denmark
- Cezary Cybulski
- International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland
- Eli Marie Grindedal
- Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway
- Jong Y. Park
- Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
- Sue A. Ingles
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90015, USA
- Christiane Maier
- Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076 Tuebingen, Germany
- Robert J. Hamilton
- Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada
- Barry S. Rosenstein
- 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
- Ana Vega
- Fundación Pública Galega Medicina Xenómica, 15706 Santiago de Compostela, Spain
- The IMPACT Study Steering Committee and Collaborators
- The Institute of Cancer Research, London SW7 3RP, UK
- Manolis Kogevinas
- ISGlobal, 08036 Barcelona, Spain
- Fredrik Wiklund
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm, Sweden
- Kathryn L. Penney
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA 02184, USA
- Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Esther M. John
- Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, USA
- Radka Kaneva
- Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria
- Christopher J. Logothetis
- Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
- Susan L. Neuhausen
- Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
- Kim De Ruyck
- Faculty of Medicine and Health Sciences, Basic Medical Sciences, Ghent University, Proeftuinstraat 86, 9000 Gent, Belgium
- Azad Razack
- Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Lisa F. Newcomb
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, DC 98109-1024, USA
- Canary PASS Investigators
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, DC 98109-1024, USA
- Davor Lessel
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Nawaid Usmani
- Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
- Frank Claessens
- Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, Campus Gasthuisberg, University of Leuven, Herestraat 49, P.O. Box 901, 3000 Leuven, Belgium
- Manuela Gago-Dominguez
- 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
- Paul A. Townsend
- 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
- Monique J. Roobol
- Department of Urology, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands
- The Profile Study Steering Committee
- Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK
- The PRACTICAL Consortium
- Manuel R. Teixeira
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
- DOI
- https://doi.org/10.3390/cancers12113254
- Journal volume & issue
-
Vol. 12,
no. 11
p. 3254
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.
Keywords