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

by 1, 1, 1, 1, 2, 1, 1, 2, 3,4, 3, 5,6, 7,†, 8,9, 10, 11,12, 13,14, 13,14, 15, 16,17,18, 19,20, 21, 22,23,24, 25,26, 27, 28, 29, 30,31, 32, 33, 19,20, 34, 35,36, 27, 27, 37,38, 39, 40, 41, 42, 43, 44,45, 46,47, 48,49,50, 7,‡, 51,52,53,54, 15, 55, 56,57,58, 59, 60, 61, 62, 63, 64, 30,65, 30,65, 66, 67,68, 69, 70,71, 72, 73, 74,§, and 1,2,6,75,*add Show full author list remove Hide full author list
Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal
The Institute of Cancer Research, London SM2 5NG, UK
Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK
Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester M13 9PL, UK
Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
The Institute of Cancer Research, London SW7 3RP, UK
Institute of Biomedicine, University of Turku, FI-20014 Turun Yliopisto, 20050 Turku, Finland
Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, P.O. Box 52, 20521 Turku, Finland
Department of Population Science, American Cancer Society, 250 Williams Street, Atlanta, GA 30303, USA
Department of Applied Health Research, University College London, London WC1E 7HB, UK
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK
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
Translational Research Institute, Brisbane, QLD 4102, Australia
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm, Sweden
Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
Department of Oncology, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK
Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200 Copenhagen, Denmark
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M3-C102, Seattle, WA 98109-1024, USA
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia
Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC 3004, Australia
Department of Clinical Pathology, The Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3004, Australia
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, ML 20892, USA
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
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, DC 98109-1024, USA
Department of Epidemiology, School of Public Health, University of Washington, Seattle, DC 98195, USA
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA
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
Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA
Sorbonne Universite, GRC n 5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-75020 Paris, France
CeRePP, Tenon Hospital, F-75020 Paris, France
Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200 Aarhus N, Denmark
Department of Clinical Medicine, Aarhus University, DK-8200 Aarhus N, Denmark
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland
Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway
Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90015, USA
Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076 Tuebingen, Germany
Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada
Department of Surgery (Urology), University of Toronto, Toronto, ON M5T 1P5, Canada
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
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA
Fundación Pública Galega Medicina Xenómica, 15706 Santiago de Compostela, Spain
Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago De Compostela, Spain
CIBER of Rare Diseases (CIBERER), 28029 Madrid, Spain
ISGlobal, 08036 Barcelona, Spain
IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
Campus del Mar, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain
CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA 02184, USA
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, USA
Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria
Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
Faculty of Medicine and Health Sciences, Basic Medical Sciences, Ghent University, Proeftuinstraat 86, 9000 Gent, Belgium
Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
Department of Urology, University of Washington, 1959 NE Pacific Street, Box 356510, Seattle, WA 98195, USA
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
Division of Radiation Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, Campus Gasthuisberg, University of Leuven, Herestraat 49, P.O. Box 901, 3000 Leuven, Belgium
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
Moores Cancer Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92093-0012, USA
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
Department of Urology, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands
Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK
Biomedical Sciences Institute Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
Author to whom correspondence should be addressed.
Further information on The PRACTICAL Consortium is provided in the Supplementary Information.
Cancers 2020, 12(11), 3254;
Received: 15 September 2020 / Revised: 19 October 2020 / Accepted: 20 October 2020 / Published: 4 November 2020
It is well-recognised the strong contribution of genetic factors to prostate cancer (PrCa) susceptibility, thus genetic screening is critical for presymptomatic diagnosis and identification of individuals at high-risk. In this context, recurrent founder variants in cancer predisposing genes, by providing specific targets for early identification of carriers at risk of developing the disease, may be leveraged to implement cost-efficient targeted genetic screening strategies. The goal of this study was to investigate whether CHEK2 c.349A>G, the only recurrent “likely pathogenic” variant in CHEK2 gene reported in the Portuguese population, plays an important role in PrCa development, and the possibility of a founder effect behind its origin. Our results clearly demonstrate that c.349A>G in the CHEK2 tumour-suppressor gene is a founder variant significantly associated with an increased risk of PrCa, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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. View Full-Text
Keywords: prostate cancer; founder variant; CHEK2; cancer predisposition prostate cancer; founder variant; CHEK2; cancer predisposition
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Figure 1

MDPI and ACS Style

Brandão, A.; Paulo, P.; Maia, S.; Pinheiro, M.; Peixoto, A.; Cardoso, M.; Silva, M.P.; Santos, C.; Eeles, R.A.; Kote-Jarai, Z.; Muir, K.; UKGPCS Collaborators; Schleutker, J.; Wang, Y.; Pashayan, N.; Batra, J.; APCB BioResource; Grönberg, 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.; Sørensen, K.D.; Cybulski, C.; Grindedal, E.M.; Park, J.Y.; Ingles, S.A.; Maier, C.; Hamilton, R.J.; Rosenstein, B.S.; Vega, A.; The IMPACT Study Steering Committee and Collaborators; Kogevinas, M.; Wiklund, F.; Penney, K.L.; Brenner, H.; John, E.M.; Kaneva, R.; Logothetis, C.J.; Neuhausen, S.L.; Ruyck, K.D.; Razack, A.; Newcomb, L.F.; Canary PASS Investigators; Lessel, D.; Usmani, N.; Claessens, F.; Gago-Dominguez, M.; Townsend, P.A.; Roobol, M.J.; The Profile Study Steering Committee; The PRACTICAL Consortium; Teixeira, M.R. The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor. Cancers 2020, 12, 3254.

AMA Style

Brandão A, Paulo P, Maia S, Pinheiro M, Peixoto A, Cardoso M, Silva MP, Santos C, Eeles RA, Kote-Jarai Z, Muir K, UKGPCS Collaborators, Schleutker J, Wang Y, Pashayan N, Batra J, APCB BioResource, Grönberg H, Neal DE, Nordestgaard BG, Tangen CM, Southey MC, Wolk A, Albanes D, Haiman CA, Travis RC, Stanford JL, Mucci LA, West CML, Nielsen SF, Kibel AS, Cussenot O, Berndt SI, Koutros S, Sørensen KD, Cybulski C, Grindedal EM, Park JY, Ingles SA, Maier C, Hamilton RJ, Rosenstein BS, Vega A, The IMPACT Study Steering Committee and Collaborators, Kogevinas M, Wiklund F, Penney KL, Brenner H, John EM, Kaneva R, Logothetis CJ, Neuhausen SL, Ruyck KD, Razack A, Newcomb LF, Canary PASS Investigators, Lessel D, Usmani N, Claessens F, Gago-Dominguez M, Townsend PA, Roobol MJ, The Profile Study Steering Committee, The PRACTICAL Consortium, Teixeira MR. The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor. Cancers. 2020; 12(11):3254.

Chicago/Turabian Style

Brandão, Andreia, 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, and Manuel R. Teixeira. 2020. "The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor" Cancers 12, no. 11: 3254.

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