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https://repository.monashhealth.org/monashhealthjspui/handle/1/27353| Title: | The CHEK2 variant C.349A>G is associated with prostate cancer risk and carriers share a common ancestor. | Authors: | Neuhausen S.L.;Brandao A.;Paulo P.;Maia S.;Pinheiro M.;Peixoto A.;Cardoso M.;Silva M.P.;Santos C.;Eeles R.A.;John E.M.;Kaneva R.;Logothetis C.J.;De Ruyck K.;Razack A.;Newcomb L.F.;Lessel D.;Usmani N.;Claessens F.;Gago-Dominguez M.;Townsend P.A.;Roobol M.J.;Teixeira M.R.;Kote-Jarai Z.;Muir K.;Schleutker J.;Wang Y.;Pashayan N.;Batra J.;Gronberg H.;Neal D.E.;Nordestgaard B.G.;Tangen C.M.;Southey M.C.;Wolk A.;Albanes D.;Haiman C.A.;Travis R.C.;Stanford J.L.;Mucci L.A.;West C.M.L.;Nielsen S.F.;Kibel A.S.;Cussenot O.;Berndt S.I.;Koutros S.;Sorensen K.D.;Cybulski C.;Grindedal E.M.;Park J.Y.;Ingles S.A.;Maier C.;Hamilton R.J.;Rosenstein B.S.;Vega A.;Kogevinas M.;Wiklund F.;Penney K.L.;Brenner H. | Institution: | (Brandao, Paulo, Maia, Pinheiro, Cardoso, Silva, Teixeira) Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto 4200-072, Portugal (Peixoto, Santos, Teixeira) Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto 4200-072, Portugal (Eeles, Kote-Jarai) The Institute of Cancer Research, London SM2 5NG, United Kingdom (Eeles) Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom (Muir) Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom (Muir, Teixeira) Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom (Schleutker) Institute of Biomedicine, University of Turku, 20050, Turun Yliopisto, Turku FI-20014, Finland (Schleutker) Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, P.O. Box 52, Turku 20521, Finland (Wang) Department of Population Science, American Cancer Society, 250 Williams Street, Atlanta, GA 30303, United States (Pashayan) Department of Applied Health Research, University College London, London WC1E 7HB, United Kingdom (Pashayan) Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom (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 (Batra) Translational Research Institute, Brisbane, QLD 4102, Australia (Gronberg, Wiklund) Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm SE-171 77, Sweden (Neal) Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Room 6603, Level 6, Headley Way, Headington, Oxford OX3 9DU, United Kingdom (Neal) Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom (Neal) Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom (Nordestgaard, Nielsen) Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark (Nordestgaard, Nielsen) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Copenhagen 2200, Denmark (Tangen) SWOG Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M3-C102, Seattle, WA 98109-1024, United States (Southey) Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia (Southey) Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC 3004, Australia (Southey) Department of Clinical Pathology, The Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3004, Australia (Wolk) Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden (Wolk) Department of Surgical Sciences, Uppsala University, Uppsala 75185, Sweden (Albanes, Berndt, Koutros) Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, United States (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, United States (Travis) Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, United Kingdom (Stanford, Newcomb) Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, DC 98109-1024, United States (Stanford) Department of Epidemiology, School of Public Health, University of Washington, Seattle, DC 98195, United States (Mucci) Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, United States (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, United Kingdom (Kibel) Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, United States (Cussenot) Sorbonne Universite, GRC n 5, AP-HP, Tenon Hospital, 4 rue de la Chine, Paris F-75020, France (Cussenot) CeRePP, Tenon Hospital, Paris F-75020, France (Sorensen) Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, Aarhus N 8200, Denmark (Sorensen) Department of Clinical Medicine, Aarhus University, Aarhus N DK-8200, Denmark (Cybulski) International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland (Grindedal) Department of Medical Genetics, Oslo University Hospital, Oslo 0424, Norway (Park) Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, United States (Ingles) Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90015, United States (Maier) Humangenetik Tuebingen, Paul-Ehrlich-Str 23, Tuebingen D-72076, Germany (Hamilton) Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada (Hamilton) Department of Surgery (Urology), University of Toronto, Toronto, ON M5T 1P5, Canada (Rosenstein) Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Box 1236, One Gustave L. Levy Place, New York, NY 10029, United States (Rosenstein) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, United States (Vega) Fundacion Publica Galega Medicina Xenomica, Santiago de Compostela 15706, Spain (Vega) Health Research Institute of Santiago de Compostela (IDIS), Santiago De Compostela 15706, Spain (Vega) CIBER of Rare Diseases (CIBERER), Madrid 28029, Spain (Kogevinas) ISGlobal, Barcelona 08036, Spain (Kogevinas) IMIM (Hospital del Mar Medical Research Institute), Barcelona 08003, Spain (Kogevinas) Universitat Pompeu Fabra (UPF), Campus del Mar, Barcelona 08003, Spain (Kogevinas) CIBER Epidemiologia y Salud Publica (CIBERESP), Madrid 28029, Spain (Penney) Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02184, United States (Brenner) Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany (Brenner) German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany (Brenner) Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Heidelberg 69120, Germany (John) Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, United States (Kaneva) Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., Sofia 1431, Bulgaria (Logothetis) Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States (Neuhausen) Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, United States (De Ruyck) Faculty of Medicine and Health Sciences, Basic Medical Sciences, Ghent University, Proeftuinstraat 86, Gent 9000, Belgium (Razack) Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia (Newcomb) Department of Urology, University of Washington, 1959 NE Pacific Street, Box 356510, Seattle, WA 98195, United States (Lessel) Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany (Usmani) Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada (Usmani) Division of Radiation Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada (Claessens) Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, Campus Gasthuisberg, University of Leuven, Herestraat 49, P.O. Box 901, Leuven 3000, Belgium (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, Santiago de Compostela 15782, Spain (Gago-Dominguez) Moores Cancer Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92093-0012, United States (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, United Kingdom (Roobol) Department of Urology, Erasmus University Medical Center, Rotterdam 3015 CE, Netherlands (Teixeira) Biomedical Sciences Institute Abel Salazar (ICBAS), University of Porto, Porto 4050-313, Portugal | Issue Date: | 11-Feb-2021 | Copyright year: | 2020 | Publisher: | MDPI AG | Place of publication: | Switzerland | Publication information: | Cancers. 12 (11) (pp 1-17), 2020. Article Number: 3254. Date of Publication: November 2020. | Journal: | Cancers | 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.Copyright © 2020 by the authors. Licensee MDPI, Basel, Switzerland. | DOI: | http://monash.idm.oclc.org/login?url= http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.3390/cancers12113254 |
ISSN: | 2072-6694 (electronic) | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/27353 | Type: | Article | Subjects: | major clinical study age determination *ancestry group article *cancer risk controlled study founder effect gene frequency *genetic association *genetic variability haplotype *heterozygote human male microsatellite marker missense mutation phylogeography Portuguese (citizen) prevalence *prostate cancer single nucleotide polymorphism checkpoint kinase 2/ec [Endogenous Compound] genetic analyzer *CHEK2 gene 3500 Genetic Analyzer *heterozygote human major clinical study male microsatellite marker missense mutation phylogeography Portuguese (citizen) prevalence *prostate cancer single nucleotide polymorphism *ancestry group age determination Article *cancer risk controlled study founder effect gene frequency *genetic association *genetic variability haplotype |
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