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

TY - JOUR

T1 - The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor

AU - Brandão, Andreia

AU - Paulo, Paula

AU - Maia, Sofia

AU - Pinheiro, Manuela

AU - Peixoto, Ana

AU - Cardoso, Marta

AU - Silva, Maria P

AU - Santos, Catarina

AU - Eeles, Rosalind A

AU - Kote-Jarai, Zsofia

AU - Muir, Kenneth

AU - Ukgpcs Collaborators, null

AU - Schleutker, Johanna

AU - Wang, Ying

AU - Pashayan, Nora

AU - Batra, Jyotsna

AU - Apcb BioResource, null

AU - Grönberg, Henrik

AU - Neal, David E

AU - Nordestgaard, Børge G

AU - Tangen, Catherine M

AU - Southey, Melissa C

AU - Wolk, Alicja

AU - Albanes, Demetrius

AU - Haiman, Christopher A

AU - Travis, Ruth C

AU - Stanford, Janet L

AU - Mucci, Lorelei A

AU - West, Catharine M L

AU - Nielsen, Sune F

AU - Kibel, Adam S

AU - Cussenot, Olivier

AU - Berndt, Sonja I

AU - Koutros, Stella

AU - Sørensen, Karina Dalsgaard

AU - Cybulski, Cezary

AU - Grindedal, Eli Marie

AU - Park, Jong Y

AU - Ingles, Sue A

AU - Maier, Christiane

AU - Hamilton, Robert J

AU - Rosenstein, Barry S

AU - Vega, Ana

AU - The Impact Study Steering Committee And Collaborators, null

AU - Kogevinas, Manolis

AU - Wiklund, Fredrik

AU - Penney, Kathryn L

AU - Brenner, Hermann

AU - John, Esther M

AU - Kaneva, Radka

AU - Logothetis, Christopher J

AU - Neuhausen, Susan L

AU - Ruyck, Kim De

AU - Razack, Azad

AU - Newcomb, Lisa F

AU - Canary Pass Investigators, null

AU - Lessel, Davor

AU - Usmani, Nawaid

AU - Claessens, Frank

AU - Gago-Dominguez, Manuela

AU - Townsend, Paul A

AU - Roobol, Monique J

AU - The Profile Study Steering Committee, null

AU - The Practical Consortium, null

AU - Teixeira, Manuel R

PY - 2020/11/4

Y1 - 2020/11/4

N2 - 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.

AB - 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.

U2 - 10.3390/cancers12113254

DO - 10.3390/cancers12113254

M3 - SCORING: Journal article

C2 - 33158149

VL - 12

JO - CANCERS

JF - CANCERS

SN - 2072-6694

IS - 11

ER -