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    The CHEK2 Variant C.349A>G is associated with prostate cancer risk and carriers share a common ancestor

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    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.
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    Affiliation
    Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), 4200-072 Porto, Portugal.
    Issue Date
    2020
    
    Metadata
    Show full item record
    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.
    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
    Cancers
    URI
    http://hdl.handle.net/10541/623566
    DOI
    10.3390/cancers12113254
    PubMed ID
    33158149
    Additional Links
    https://dx.doi.org/10.3390/cancers12113254
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.3390/cancers12113254
    Scopus Count
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