The CHEK2 Variant C.349A>G is associated with prostate cancer risk and carriers share a common ancestor
Authors
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, C.
Schleutker, J.
Wang, Y.
Pashayan, N.
Batra, J.
Apcb, B.
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, Catharine 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.
Kogevinas, M.
Wiklund, F.
Penney, K. L.
Brenner, H.
John, E. M.
Kaneva, R.
Logothetis, C. J.
Neuhausen, S. L.
Ruyck, K.
Razack, A.
Newcomb, L. F.
Canary Pass, I.
Lessel, D.
Usmani, N.
Claessens, F.
Gago-Dominguez, M.
Townsend, P. A.
Roobol, M. J.
The Profile Study Steering, C.
The Practical, C.
Teixeira, M. R.
Affiliation
Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal.Issue Date
2020
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Show full item recordAbstract
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.Citation
Brandao A, Paulo P, Maia S, Pinheiro M, Peixoto A, Cardoso M, et al. The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor. Cancers (Basel). 2020;12(11).Journal
CancersDOI
10.3390/cancers12113254PubMed ID
33158149Additional Links
https://dx.doi.org/10.3390/cancers12113254Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.3390/cancers12113254
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