The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.
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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
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
Document Type
Journal Article
Date
2020-11-04
Date Accepted
2020-10-20
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.
Citation
Cancers, 2020, 12 (11)
Source Title
Publisher
MDPI
ISSN
2072-6694
eISSN
2072-6694
Research Team
Oncogenetics