| Title: |
The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor. |
| Authors: |
Brandão, Andreia; Paulo, Paula; Maia, Sofia; Pinheiro, Manuela; Peixoto, Ana; Cardoso, Marta; Silva, Maria P; Santos, Catarina; Eeles, Rosalind A; Kote-Jarai, Zsofia; Muir, Kenneth; Ukgpcs Collaborators; Schleutker, Johanna; Wang, Ying; Pashayan, Nora; Batra, Jyotsna; Apcb BioResource; Grönberg, Henrik; Neal, David E; Nordestgaard, Børge G; Tangen, Catherine M; Southey, Melissa C; Wolk, Alicja; Albanes, Demetrius; Haiman, Christopher A; Travis, Ruth C; Stanford, Janet L; Mucci, Lorelei A; West, Catharine ML; Nielsen, Sune F; Kibel, Adam S; Cussenot, Olivier; Berndt, Sonja I; Koutros, Stella; Sørensen, Karina Dalsgaard; Cybulski, Cezary; Grindedal, Eli Marie; Park, Jong Y; Ingles, Sue A; Maier, Christiane; Hamilton, Robert J; Rosenstein, Barry S; Vega, Ana; The Impact Study Steering Committee And Collaborators; Kogevinas, Manolis; Wiklund, Fredrik; Penney, Kathryn L; Brenner, Hermann; John, Esther M; Kaneva, Radka; Logothetis, Christopher J; Neuhausen, Susan L; Ruyck, Kim De; Razack, Azad; Newcomb, Lisa F; Canary Pass Investigators; Lessel, Davor; Usmani, Nawaid; Claessens, Frank; Gago-Dominguez, Manuela; Townsend, Paul A; Roobol, Monique J; The Profile Study Steering Committee; The Practical Consortium; Teixeira, Manuel R |
| Publisher Information: |
MDPI; //doi.org/10.3390/cancers12113254 |
| Publication Year: |
2020 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
CHEK2; cancer predisposition; founder variant; prostate cancer |
| 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: |
text/xml; application/zip; application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/312570 |
| DOI: |
10.17863/CAM.59671 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/312570; https://doi.org/10.17863/CAM.59671 |
| Rights: |
Attribution 4.0 International (CC BY 4.0) ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.5DA0C7E |
| Database: |
BASE |