期刊
CANCERS
卷 12, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/cancers12113254
关键词
prostate cancer; founder variant; CHEK2; cancer predisposition
类别
资金
- IPO-Porto Research Center [CI-IPOP-16-2012]
- Fundacao para a Ciencia e a Tecnologia (FCT) [PEst-OE/SAU/ UI0776/2014, PTDC/DTP-PIC/1308/2014]
- FCT [UID/DTP/00776/2013/POCI-01-0145-FEDER-006868, SFRH/BD/71397/2010, SFRH/BD/73719/2010]
- Canadian Institutes of Health Research
- European Commission [223175 (HEALTH-F2-2009-223175)]
- Cancer Research UK [C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, A8197/A16565]
- National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative [1 U19 CA 148537-01]
- US National Institutes of Health (NIH) [U19 CA 148537, X01HG007492, HHSN268201200008I]
- NIH NCI [U01 CA188392]
- Institute of Cancer Research
- Everyman Campaign
- Prostate Cancer Research Foundation
- PCUK
- Orchid Cancer Appeal
- Rosetrees Trust
- National Cancer Research Network UK
- National Cancer Research Institute (NCRI) UK
- NIHR
- Fundação para a Ciência e a Tecnologia [SFRH/BD/73719/2010, PEst-OE/SAU/UI0776/2014, SFRH/BD/71397/2010, PTDC/DTP-PIC/1308/2014] Funding Source: FCT
Simple Summary It is well-recognised the strong contribution of genetic factors to prostate cancer (PrCa) susceptibility, thus genetic screening is critical for presymptomatic diagnosis and identification of individuals at high-risk. In this context, recurrent founder variants in cancer predisposing genes, by providing specific targets for early identification of carriers at risk of developing the disease, may be leveraged to implement cost-efficient targeted genetic screening strategies. The goal of this study was to investigate whether CHEK2 c.349A>G, the only recurrent likely pathogenic variant in CHEK2 gene reported in the Portuguese population, plays an important role in PrCa development, and the possibility of a founder effect behind its origin. Our results clearly demonstrate that c.349A>G in the CHEK2 tumour-suppressor gene is a founder variant significantly associated with an increased risk of PrCa, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families. 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.
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