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

Brandão, Andreia; Kogevinas, Manolis; Teixeira, Manuel R.

doi:http://dx.doi.org/10.3390/cancers12113254

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

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Brandão 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 Nov 4; 12(11): 3254. 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.