The CHEK2 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; Johanna Schleutker; Ying Wang; Nora Pashayan; Jyotsna Batra; 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; 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; Paul A Townsend; Davor Lessel; Nawaid Usmani; Frank Claessens; Manuela Gago-Dominguez; Monique J Roobol; Manuel R Teixeira

doi:10.3390/cancers12113254

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

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The CHEK2 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, …

Cancers, Vol.12(11), 3254

04/11/2020

DOI: https://doi.org/10.3390/cancers12113254

PMID: 33158149

Abstract

cancer predisposition

founder variant

CHEK2

Prostate Cancer

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.

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Title: The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor
Creators: 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
Johanna Schleutker - Institute of Biomedicine, University of Turku, FI-20014 Turun Yliopisto, 20050 Turku, Finland
Ying Wang - American Cancer Society
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
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
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
Paul A Townsend - University of Surrey, Faculty of Health and Medical Sciences
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
Monique J Roobol - Department of Urology, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands
Manuel R Teixeira - Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
Publication Details: Cancers, Vol.12(11), 3254
Publisher: MDPI
Date published: 04/11/2020
Date accepted: 20/10/2020
Identifiers: 99546922002346
Academic Unit: Faculty of Health and Medical Sciences; School of Sustainability, Civil and Environmental Engineering
Language: English
Resource Type: Journal article

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

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