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

• Type: Article in International Scientific Journal
• Date: 2020

Authors

Brandao, A (Author) Other; Paulo, P (Author) Other; Maia, S (Author) Other; Pinheiro, M (Author) Other; Peixoto, A (Author) Other; Cardoso, M (Author) Other; Silva, MP (Author) Other; Santos, C (Author) Other; Eeles, RA (Author) Other; Kote Jarai, Z (Author) Other; Muir, K (Author) Other; Schleutker, J (Author) Other; Wang, Y (Author) Other; Pashayan, N (Author) Other; Batra, J (Author) Other; Gronberg, H (Author) Other; Neal, DE (Author) Other; Nordestgaard, BG (Author) Other; Tangen, CM (Author) Other; Southey, MC (Author) Other; Wolk, A (Author) Other; Albanes, D (Author) Other; Haiman, CA (Author) Other; Travis, RC (Author) Other; Stanford, JL (Author) Other; Mucci, LA (Author) Other; West, CML (Author) Other; Nielsen, SF (Author) Other; Kibel, AS (Author) Other; Cussenot, O (Author) Other; Berndt, SI (Author) Other; Koutros, S (Author) Other; Sorensen, KD (Author) Other; Cybulski, C (Author) Other; Grindedal, EM (Author) Other; Park, JY (Author) Other; Ingles, SA (Author) Other; Maier, C (Author) Other; Hamilton, RJ (Author) Other; Rosenstein, BS (Author) Other; Vega, A (Author) Other; Kogevinas, M (Author) Other; Wiklund, F (Author) Other; Penney, KL (Author) Other; Brenner, H (Author) Other; John, EM (Author) Other; Kaneva, R (Author) Other; Logothetis, CJ (Author) Other; Neuhausen, SL (Author) Other; De Ruyck, K (Author) Other; Razack, A (Author) Other; Newcomb, LF (Author) Other; Lessel, D (Author) Other; Usmani, N (Author) Other; Claessens, F (Author) Other; Gago Dominguez, M (Author) Other; Townsend, PA (Author) Other; Roobol, MJ (Author) Other; Manuel R Teixeira (Author) ICBAS

Journal

Title: Cancers

Vol. 12

Pages: 1-17

ISSN: 2072-6694

Publisher: MDPI

Indexing

ISI Web of Knowledge - 4 Citations

Scopus - 3 Citations

Other information

Authenticus ID: P-00T-2PM

DOI: 10.3390/cancers12113254

Abstract (EN): Simple Summary It is well-recognised the strong contribution of genetic factors to prostate cancer (PrCa) susceptibility, thus genetic screening is critical for presymptomatic diagnosis and identification of individuals at high-risk. In this context, recurrent founder variants in cancer predisposing genes, by providing specific targets for early identification of carriers at risk of developing the disease, may be leveraged to implement cost-efficient targeted genetic screening strategies. The goal of this study was to investigate whether CHEK2 c.349A>G, the only recurrent "likely pathogenic" variant in CHEK2 gene reported in the Portuguese population, plays an important role in PrCa development, and the possibility of a founder effect behind its origin. Our results clearly demonstrate that c.349A>G in the CHEK2 tumour-suppressor gene is a founder variant significantly associated with an increased risk of PrCa, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families. 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17