Journal Article

DKFZ-2020-02405

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Brandão, A. ; Paulo, P. ; Maia, S. ; Pinheiro, M. ; Peixoto, A. ; Cardoso, M. ; Silva, M. P. ; Santos, C. ; Eeles, R. A. ; Kote-Jarai, Z. ; Muir, K. ; Ukgpcs Collaborators ; Schleutker, J. ; Wang, Y. ; Pashayan, N. ; Batra, J. ; Apcb BioResource ; Grönberg, H. ; Neal, D. E. ; Nordestgaard, B. G. ; Tangen, C. M. ; Southey, M. C. ; Wolk, A. ; Albanes, D. ; Haiman, C. A. ; Travis, R. C. ; Stanford, J. L. ; Mucci, L. A. ; West, C. M. L. ; Nielsen, S. F. ; Kibel, A. S. ; Cussenot, O. ; Berndt, S. I. ; Koutros, S. ; Sørensen, K. D. ; Cybulski, C. ; Grindedal, E. M. ; Park, J. Y. ; Ingles, S. A. ; Maier, C. ; Hamilton, R. J. ; Rosenstein, B. S. ; Vega, A. ; The Impact Study Steering Committee And Collaborators ; Kogevinas, M. ; Wiklund, F. ; Penney, K. L. ; Brenner, H.DKFZ* ; John, E. M. ; Kaneva, R. ; Logothetis, C. J. ; Neuhausen, S. L. ; Ruyck, K. D. ; Razack, A. ; Newcomb, L. F. ; Canary Pass Investigators ; Lessel, D. ; Usmani, N. ; Claessens, F. ; Gago-Dominguez, M. ; Townsend, P. A. ; Roobol, M. J. ; The Profile Study Steering Committee ; The Practical Consortium ; Teixeira, M. R.

2020
MDPI Basel

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Please use a persistent id in citations: doi:10.3390/cancers12113254

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.

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Contributing Institute(s):

1. C070 Klinische Epidemiologie und Alternf. (C070)
2. Präventive Onkologie (C120)
3. DKTK HD zentral (HD01)

Research Program(s):

1. 313 - Cancer risk factors and prevention (POF3-313) (POF3-313)

Appears in the scientific report 2020

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Database coverage:
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