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. SoutheyAlicja 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, Davor Lessel, Nawaid Usmani, Frank Claessens, Manuela Gago-Dominguez, Paul A. Townsend, Monique J. Roobol, Manuel R. Teixeira, UKGPCS Collaborators, Canary PASS Investigators, The PROFILE Study Steering Committee, The PRACTICAL consortium

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15 Citations (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.

Original languageEnglish
Article number3254
Pages (from-to)1-17
Number of pages17
Issue number11
Publication statusPublished - Nov 2020


  • Cancer predisposition
  • CHEK2
  • Founder variant
  • Prostate cancer

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