Dataset Information

The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

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.

SUBMITTER: Brandao A

PROVIDER: S-EPMC7694218 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The <i>CHEK2</i> Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Brandão Andreia A Paulo Paula P Maia Sofia S Pinheiro Manuela M Peixoto Ana A Cardoso Marta M Silva Maria P MP Santos Catarina C Eeles Rosalind A RA Kote-Jarai Zsofia Z Muir Kenneth K Ukgpcs Collaborators Schleutker Johanna J Wang Ying Y Pashayan Nora N Batra Jyotsna J Apcb BioResource Grönberg Henrik H Neal David E DE Nordestgaard Børge G BG Tangen Catherine M CM Southey Melissa C MC Wolk Alicja A Albanes Demetrius D Haiman Christopher A CA Travis Ruth C RC Stanford Janet L JL Mucci Lorelei A LA West Catharine M L CML Nielsen Sune F SF Kibel Adam S AS Cussenot Olivier O Berndt Sonja I SI Koutros Stella S Sørensen Karina Dalsgaard KD Cybulski Cezary C Grindedal Eli Marie EM Park Jong Y JY Ingles Sue A SA Maier Christiane C Hamilton Robert J RJ Rosenstein Barry S BS Vega Ana A The Impact Study Steering Committee And Collaborators Kogevinas Manolis M Wiklund Fredrik F Penney Kathryn L KL Brenner Hermann H John Esther M EM Kaneva Radka R Logothetis Christopher J CJ Neuhausen Susan L SL Ruyck Kim De K Razack Azad A Newcomb Lisa F LF Canary Pass Investigators Lessel Davor D Usmani Nawaid N Claessens Frank F Gago-Dominguez Manuela M Townsend Paul A PA Roobol Monique J MJ The Profile Study Steering Committee The Practical Consortium Teixeira Manuel R MR

Cancers 20201104 11

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 <i>CHEK2</i> 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 ...[more]

PMID: 33158149

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Project description:PurposeCHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.Patients and methodsCHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies.ResultsProportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom.ConclusionThese CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.

Dataset Information

The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Publications

The <i>CHEK2</i> Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

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