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

Andreia Brandão¹, Paula Paulo¹, Sofia Maia¹, Manuela Pinheiro¹, Ana Peixoto², Marta Cardoso¹, Maria P Silva¹, Catarina Santos², Rosalind A Eeles^{3

4}, Zsofia Kote-Jarai³, Kenneth Muir^{5

6}, Ukgpcs Collaborators⁷, Johanna Schleutker^{8

9}, Ying Wang¹⁰, Nora Pashayan^{11

12}, Jyotsna Batra^{13

14}, Apcb BioResource^{13

14}, Henrik Grönberg¹⁵, David E Neal^{16

17

18}, Børge G Nordestgaard^{19

20}, Catherine M Tangen²¹, Melissa C Southey^{22

23

24}, Alicja Wolk^{25

26}, Demetrius Albanes²⁷, Christopher A Haiman²⁸, Ruth C Travis²⁹, Janet L Stanford^{30

31}, Lorelei A Mucci³², Catharine M L West³³, Sune F Nielsen^{19

20}, Adam S Kibel³⁴, Olivier Cussenot^{35

36}, Sonja I Berndt²⁷, Stella Koutros²⁷, Karina Dalsgaard Sørensen^{37

38}, Cezary Cybulski³⁹, Eli Marie Grindedal⁴⁰, Jong Y Park⁴¹, Sue A Ingles⁴², Christiane Maier⁴³, Robert J Hamilton^{44

45}, Barry S Rosenstein^{46

47}, Ana Vega^{48

49

50}, The Impact Study Steering Committee And Collaborators⁷, Manolis Kogevinas^{51

52

53

54}, Fredrik Wiklund¹⁵, Kathryn L Penney⁵⁵, Hermann Brenner^{56

57

58}, Esther M John⁵⁹, Radka Kaneva⁶⁰, Christopher J Logothetis⁶¹, Susan L Neuhausen⁶², Kim De Ruyck⁶³, Azad Razack⁶⁴, Lisa F Newcomb^{30

65}, Canary Pass Investigators^{30

65}, Davor Lessel⁶⁶, Nawaid Usmani^{67

68}, Frank Claessens⁶⁹, Manuela Gago-Dominguez^{70

71}, Paul A Townsend⁷², Monique J Roobol⁷³, The Profile Study Steering Committee⁷⁴, The Practical Consortium, Manuel R Teixeira^{1

2

6

75}

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 Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
⁵ Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
⁶ Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
⁷ The Institute of Cancer Research, London SW7 3RP, UK.
⁸ Institute of Biomedicine, University of Turku, FI-20014 Turun Yliopisto, 20050 Turku, Finland.
⁹ Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, P.O. Box 52, 20521 Turku, Finland.
¹⁰ Department of Population Science, American Cancer Society, 250 Williams Street, Atlanta, GA 30303, USA.
¹¹ Department of Applied Health Research, University College London, London WC1E 7HB, UK.
¹² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
¹³ 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.
¹⁴ Translational Research Institute, Brisbane, QLD 4102, Australia.
¹⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm, Sweden.
¹⁶ Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.
¹⁷ Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
¹⁸ Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
¹⁹ Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
²⁰ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200 Copenhagen, Denmark.
²¹ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M3-C102, Seattle, WA 98109-1024, USA.
²² Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
²³ Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC 3004, Australia.
²⁴ Department of Clinical Pathology, The Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3004, Australia.
²⁵ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
²⁶ Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden.
²⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, ML 20892, USA.
²⁸ 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.
²⁹ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
³⁰ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, DC 98109-1024, USA.
³¹ Department of Epidemiology, School of Public Health, University of Washington, Seattle, DC 98195, USA.
³² Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
³³ 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.
³⁴ Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA.
³⁵ Sorbonne Universite, GRC n 5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-75020 Paris, France.
³⁶ CeRePP, Tenon Hospital, F-75020 Paris, France.
³⁷ Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200 Aarhus N, Denmark.
³⁸ Department of Clinical Medicine, Aarhus University, DK-8200 Aarhus N, Denmark.
³⁹ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland.
⁴⁰ Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
⁴¹ Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁴² Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90015, USA.
⁴³ Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076 Tuebingen, Germany.
⁴⁴ Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
⁴⁵ Department of Surgery (Urology), University of Toronto, Toronto, ON M5T 1P5, Canada.
⁴⁶ 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.
⁴⁷ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.
⁴⁸ Fundación Pública Galega Medicina Xenómica, 15706 Santiago de Compostela, Spain.
⁴⁹ Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago De Compostela, Spain.
⁵⁰ CIBER of Rare Diseases (CIBERER), 28029 Madrid, Spain.
⁵¹ ISGlobal, 08036 Barcelona, Spain.
⁵² IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain.
⁵³ Campus del Mar, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
⁵⁴ CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain.
⁵⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02184, USA.
⁵⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁵⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
⁵⁸ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
⁵⁹ Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, USA.
⁶⁰ Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria.
⁶¹ Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
⁶² Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
⁶³ Faculty of Medicine and Health Sciences, Basic Medical Sciences, Ghent University, Proeftuinstraat 86, 9000 Gent, Belgium.
⁶⁴ Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
⁶⁵ Department of Urology, University of Washington, 1959 NE Pacific Street, Box 356510, Seattle, WA 98195, USA.
⁶⁶ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁶⁷ Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
⁶⁸ Division of Radiation Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
⁶⁹ Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, Campus Gasthuisberg, University of Leuven, Herestraat 49, P.O. Box 901, 3000 Leuven, Belgium.
⁷⁰ 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.
⁷¹ Moores Cancer Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92093-0012, USA.
⁷² 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.
⁷³ Department of Urology, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands.
⁷⁴ Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
⁷⁵ Biomedical Sciences Institute Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal.

PMID: 33158149
PMCID: PMC7694218
DOI: 10.3390/cancers12113254

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

Andreia Brandão et al. Cancers (Basel). 2020.

. 2020 Nov 4;12(11):3254.

doi: 10.3390/cancers12113254.

Authors

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 Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.
⁵ Division of Population Health, Health Services Research and Primary Care, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
⁶ Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
⁷ The Institute of Cancer Research, London SW7 3RP, UK.
⁸ Institute of Biomedicine, University of Turku, FI-20014 Turun Yliopisto, 20050 Turku, Finland.
⁹ Department of Medical Genetics, Genomics, Laboratory Division, Turku University Hospital, P.O. Box 52, 20521 Turku, Finland.
¹⁰ Department of Population Science, American Cancer Society, 250 Williams Street, Atlanta, GA 30303, USA.
¹¹ Department of Applied Health Research, University College London, London WC1E 7HB, UK.
¹² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
¹³ 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.
¹⁴ Translational Research Institute, Brisbane, QLD 4102, Australia.
¹⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm, Sweden.
¹⁶ Nuffield Department of Surgical Sciences, University of Oxford, Room 6603, Level 6, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.
¹⁷ Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
¹⁸ Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
¹⁹ Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
²⁰ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200 Copenhagen, Denmark.
²¹ SWOG Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M3-C102, Seattle, WA 98109-1024, USA.
²² Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
²³ Cancer Epidemiology Division, Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC 3004, Australia.
²⁴ Department of Clinical Pathology, The Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3004, Australia.
²⁵ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
²⁶ Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden.
²⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, ML 20892, USA.
²⁸ 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.
²⁹ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
³⁰ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, DC 98109-1024, USA.
³¹ Department of Epidemiology, School of Public Health, University of Washington, Seattle, DC 98195, USA.
³² Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
³³ 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.
³⁴ Division of Urologic Surgery, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA.
³⁵ Sorbonne Universite, GRC n 5, AP-HP, Tenon Hospital, 4 rue de la Chine, F-75020 Paris, France.
³⁶ CeRePP, Tenon Hospital, F-75020 Paris, France.
³⁷ Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensen Boulevard 99, 8200 Aarhus N, Denmark.
³⁸ Department of Clinical Medicine, Aarhus University, DK-8200 Aarhus N, Denmark.
³⁹ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland.
⁴⁰ Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
⁴¹ Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.
⁴² Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90015, USA.
⁴³ Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076 Tuebingen, Germany.
⁴⁴ Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
⁴⁵ Department of Surgery (Urology), University of Toronto, Toronto, ON M5T 1P5, Canada.
⁴⁶ 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.
⁴⁷ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.
⁴⁸ Fundación Pública Galega Medicina Xenómica, 15706 Santiago de Compostela, Spain.
⁴⁹ Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago De Compostela, Spain.
⁵⁰ CIBER of Rare Diseases (CIBERER), 28029 Madrid, Spain.
⁵¹ ISGlobal, 08036 Barcelona, Spain.
⁵² IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain.
⁵³ Campus del Mar, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
⁵⁴ CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain.
⁵⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02184, USA.
⁵⁶ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
⁵⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
⁵⁸ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.
⁵⁹ Departments of Epidemiology & Population Health and of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, USA.
⁶⁰ Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, 2 Zdrave Str., 1431 Sofia, Bulgaria.
⁶¹ Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
⁶² Department of Population Sciences, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
⁶³ Faculty of Medicine and Health Sciences, Basic Medical Sciences, Ghent University, Proeftuinstraat 86, 9000 Gent, Belgium.
⁶⁴ Department of Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
⁶⁵ Department of Urology, University of Washington, 1959 NE Pacific Street, Box 356510, Seattle, WA 98195, USA.
⁶⁶ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁶⁷ Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
⁶⁸ Division of Radiation Oncology, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
⁶⁹ Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, Campus Gasthuisberg, University of Leuven, Herestraat 49, P.O. Box 901, 3000 Leuven, Belgium.
⁷⁰ 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.
⁷¹ Moores Cancer Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92093-0012, USA.
⁷² 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.
⁷³ Department of Urology, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands.
⁷⁴ Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
⁷⁵ Biomedical Sciences Institute Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal.

PMID: 33158149
PMCID: PMC7694218
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.

Keywords: CHEK2; cancer predisposition; founder variant; prostate cancer.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

**Figure 1**
Shared identity-by-descent (IBD) haplotype between all carriers of the *CHEK2* variant c.349A>G. (A). Shared IBD segments by populations: Australia, Portugal, Scandinavia (Denmark and Sweden), Spain, Western/Central Europe populations (Belgium, France, Germany and Netherlands), UK, and U.S. (B) Characterisation of IBD core segment shared by all carriers (≈0.4 Mb in detail, represented in light orange in Figure 1A). (C) Median joining phylogenetic tree of the largest shared haplotype region flanking the *CHEK2* variant c.349A>G between all carriers (indicated in light grey in Figure 1A).

**Figure 2**
Overall age estimation of the *CHEK2* variant c.349A>G using the DMLE+2.3 software, considering the 70 carriers. Distribution of the posterior probability for the age estimation, assuming 0.00028 as the proportion of variant-carrying chromosomes and the two population growth rates 0.10 and 0.13.

**Figure 3**
Possible geographic dispersal scenario inferred from present data of the populations carrying *CHEK2* variant c.349A>G, with the average age estimates obtained by DMLE+2.3, using the two population growth rates. Background map adapted from the map outline published under the terms of the GNU Free Documentation License, Version 1.2 [28].

See this image and copyright information in PMC

References

1. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. - DOI - PubMed
1. Bashir M.N. Epidemiology of prostate cancer. Asian Pac. J. Cancer Prev. 2015;16:5137–5141. doi: 10.7314/APJCP.2015.16.13.5137. - DOI - PubMed
1. Al Olama A.A., Kote-Jarai Z., Schumacher F.R., Wiklund F., Berndt S.I., Benlloch S., Giles G.G., Severi G., Neal D.E., Hamdy F.C., et al. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease. Hum. Mol. Genet. 2013;22:408–415. doi: 10.1093/hmg/dds425. - DOI - PMC - PubMed
1. Schumacher F.R., Al Olama A.A., Berndt S.I., Benlloch S., Ahmed M., Saunders E.J., Dadaev T., Leongamornlert D., Anokian E., Cieza-Borrella C., et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat. Genet. 2018;50:928–936. doi: 10.1038/s41588-018-0142-8. - DOI - PMC - PubMed
1. Al Olama A.A., Kote-Jarai Z., Giles G.G., Guy M., Morrison J., Severi G., Leongamornlert D.A., Tymrakiewicz M., Jhavar S., Saunders E., et al. Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat. Genet. 2009;41:1058–1060. doi: 10.1038/ng.452. - DOI - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- ClinicalTrials.gov

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Medical