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, Ukgpcs Collaborators, Johanna Schleutker, Ying Wang, Nora Pashayan, Jyotsna Batra, Apcb BioResource, Henrik Grönberg, David E Neal, Børge G NordestgaardCatherine 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

12 Citationer (Scopus)


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.

Udgave nummer11
Sider (fra-til)1-17
Antal sider17
StatusUdgivet - 4 nov. 2020


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