| Title: |
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, MP; Santos, C; Eeles, RA; Kote-Jarai, Z; Muir, K; Ukgpcs Collaborators; Schleutker, J; Wang, Y; Pashayan, N; Batra, J; Apcb BioResource; Grönberg, H; Neal, DE; Nordestgaard, BG; Tangen, CM; Southey, MC; Wolk, A; Albanes, D; Haiman, CA; Travis, RC; Stanford, JL; Mucci, LA; West, CML; Nielsen, SF; Kibel, AS; Cussenot, O; Berndt, SI; Koutros, S; Sørensen, KD; Cybulski, C; Grindedal, EM; Park, JY; Ingles, SA; Maier, C; Hamilton, RJ; Rosenstein, BS; Vega, A; The Impact Study Steering Committee And Collaborators; Kogevinas, M; Wiklund, F; Penney, KL; Brenner, H; John, EM; Kaneva, R; Logothetis, CJ; Neuhausen, SL; Ruyck, KD; Razack, A; Newcomb, LF; Canary Pass Investigators; Lessel, D; Usmani, N; Claessens, F; Gago-Dominguez, M; Townsend, PA; Roobol, MJ; The Profile Study Steering Committee; The Practical Consortium; Teixeira, MR |
| Contributors: |
Eeles, Rosalind; Kote-Jarai, Zsofia |
| Publisher Information: |
MDPI |
| Publication Year: |
2021 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Electronic; application/vnd.openxmlformats-officedocument.wordprocessingml.document |
| Language: |
English |
| ISSN: |
2072-6694 |
| Relation: |
Cancers, 2020, 12 (11); https://repository.icr.ac.uk/handle/internal/4296 |
| DOI: |
10.3390/cancers12113254 |
| Availability: |
https://doi.org/10.3390/cancers12113254; https://repository.icr.ac.uk/handle/internal/4296 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.FC5F7AC7 |
| Database: |
BASE |