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 - Schleutker, Johanna
AU - Wang, Ying
AU - Pashayan, Nora
AU - Batra, Jyotsna
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 - 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 - De Ruyck, Kim
AU - Razack, Azad
AU - Newcomb, Lisa F.
AU - Lessel, Davor
AU - Usmani, Nawaid
AU - Claessens, Frank
AU - Gago-Dominguez, Manuela
AU - Townsend, Paul A.
AU - Roobol, Monique J.
AU - Teixeira, Manuel R.
AU - UKGPCS Collaborators
AU - Canary PASS Investigators
AU - The PROFILE Study Steering Committee
AU - The PRACTICAL consortium
N1 - Funding Information:
We thank the funding support from IPO-Porto Research Center (CI-IPOP-16-2012) and from Fundação para a Ciência e a Tecnologia (FCT; PEst-OE/SAU/ UI0776/2014 and PTDC/DTP-PIC/1308/2014). The following authors were awarded with grants from FCT: PPa (UID/DTP/00776/2013/POCI-01-0145-FEDER-006868), SM (SFRH/BD/71397/2010) and PPi (SFRH/BD/73719/2010). The PRACTICAL consortium (http://practical.icr.ac.uk/) was supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme grant agreement n◦ 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA 148537-01 (the GAME-ON initiative). Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) [U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I] and by Cancer Research UK grant A8197/A16565. Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher). We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now PCUK), The Orchid Cancer Appeal, Rosetrees Trust, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, NIHR funding to the Manchester Biomedical Research Centre and the Manchester Academic Health Sciences Centre. Acknowledgments: We wish to thank all the patients and their relatives who took part in this study. We would also like to thank Emmanuelle Genin for kindly providing the source code and documentation for the ESTIAGE software.
Funding Information:
Funding: We thank the funding support from IPO-Porto Research Center (CI-IPOP-16-2012) and from Fundação para a Ciência e a Tecnologia (FCT; PEst-OE/SAU/ UI0776/2014 and PTDC/DTP-PIC/1308/2014). The following authors were awarded with grants from FCT: PPa (UID/DTP/00776/2013/POCI-01-0145-FEDER-006868), SM (SFRH/BD/71397/2010) and PPi (SFRH/BD/73719/2010). The PRACTICAL consortium (http://practical.icr.ac.uk/) was supported by the Canadian Institutes of Health Research, European Commission’s Seventh Framework Programme grant agreement n◦ 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA 148537-01 (the GAME-ON initiative). Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) [U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I] and by Cancer Research UK grant A8197/A16565. Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher). We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now PCUK), The Orchid Cancer Appeal, Rosetrees Trust, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, NIHR funding to the Manchester Biomedical Research Centre and the Manchester Academic Health Sciences Centre.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/11
Y1 - 2020/11
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.
KW - Cancer predisposition
KW - CHEK2
KW - Founder variant
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85096384312&partnerID=8YFLogxK
U2 - 10.3390/cancers12113254
DO - 10.3390/cancers12113254
M3 - Article
C2 - 33158149
AN - SCOPUS:85096384312
SN - 2072-6694
VL - 12
SP - 1
EP - 17
JO - Cancers
JF - Cancers
IS - 11
M1 - 3254
ER -
