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

Andreia Brandão; Paula Paulo; Sofia Maia; Manuela Pinheiro; Ana Peixoto; Marta Cardoso; Maria P Silva; Catarina Santos; Rosalind A Eeles; Zsofia Kote-Jarai; Kenneth Muir; null Ukgpcs Collaborators; Johanna Schleutker; Ying Wang; Nora Pashayan; Jyotsna Batra; null Apcb BioResource; Henrik Grönberg; David E Neal; Børge G Nordestgaard; Catherine M Tangen; Melissa C Southey; Alicja Wolk; Demetrius Albanes; Christopher A Haiman; Ruth C Travis; Janet L Stanford; Lorelei A Mucci; Catharine M L West; Sune F Nielsen; Adam S Kibel; Olivier Cussenot; Sonja I Berndt; Stella Koutros; Karina Dalsgaard Sørensen; Cezary Cybulski; Eli Marie Grindedal; Jong Y Park; Sue A Ingles; Christiane Maier; Robert J Hamilton; Barry S Rosenstein; Ana Vega; null The Impact Study Steering Committee And Collaborators; Manolis Kogevinas; Fredrik Wiklund; Kathryn L Penney; Hermann Brenner; Esther M John; Radka Kaneva; Christopher J Logothetis; Susan L Neuhausen; Kim De Ruyck; Azad Razack; Lisa F Newcomb; null Canary Pass Investigators; Davor Lessel; Nawaid Usmani; Frank Claessens; Manuela Gago-Dominguez; Paul A Townsend; Monique J Roobol; null The Profile Study Steering Committee; null The Practical Consortium; Manuel R Teixeira

doi:10.3390/cancers12113254

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

Andreia Brandão, Paula Paulo, Sofia Maia, Manuela Pinheiro, Ana Peixoto, Marta Cardoso, Maria P Silva, Catarina Santos, Rosalind A Eeles, Zsofia Kote-Jarai, Kenneth Muir, Ukgpcs Collaborators, Johanna Schleutker, Ying Wang, Nora Pashayan, Jyotsna Batra, Apcb BioResource, Henrik Grönberg, David E Neal, Børge G NordestgaardCatherine M Tangen, Melissa C Southey, Alicja Wolk, Demetrius Albanes, Christopher A Haiman, Ruth C Travis, Janet L Stanford, Lorelei A Mucci, Catharine M L West, Sune F Nielsen, Adam S Kibel, Olivier Cussenot, Sonja I Berndt, Stella Koutros, Karina Dalsgaard Sørensen, Cezary Cybulski, Eli Marie Grindedal, Jong Y Park, Sue A Ingles, Christiane Maier, Robert J Hamilton, Barry S Rosenstein, Ana Vega, The Impact Study Steering Committee And Collaborators, Manolis Kogevinas, Fredrik Wiklund, Kathryn L Penney, Hermann Brenner, Esther M John, Radka Kaneva, Christopher J Logothetis, Susan L Neuhausen, Kim De Ruyck, Azad Razack, Lisa F Newcomb, Canary Pass Investigators, Davor Lessel, Nawaid Usmani, Frank Claessens, Manuela Gago-Dominguez, Paul A Townsend, Monique J Roobol, The Profile Study Steering Committee, The Practical Consortium, Manuel R Teixeira

Klinisk Biokemisk afd.

12 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	3254
Tidsskrift	Cancers
Vol/bind	12
Udgave nummer	11
Sider (fra-til)	1-17
Antal sider	17
ISSN	2072-6694
DOI	https://doi.org/10.3390/cancers12113254
Status	Udgivet - 4 nov. 2020

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10.3390/cancers12113254

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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., ... Teixeira, M. R. (2020). The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor. Cancers, 12(11), 1-17. [3254]. https://doi.org/10.3390/cancers12113254

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 2020, 'The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor', Cancers, bind 12, nr. 11, 3254, s. 1-17. https://doi.org/10.3390/cancers12113254

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

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.",

keywords = "Cancer predisposition, CHEK2, Founder variant, Prostate cancer",

author = "Andreia Brand{\~a}o and Paula Paulo and Sofia Maia and Manuela Pinheiro and Ana Peixoto and Marta Cardoso and Silva, {Maria P} and Catarina Santos and Eeles, {Rosalind A} and Zsofia Kote-Jarai and Kenneth Muir and {Ukgpcs Collaborators} and Johanna Schleutker and Ying Wang and Nora Pashayan and Jyotsna Batra and {Apcb BioResource} and Henrik Gr{\"o}nberg and Neal, {David E} and Nordestgaard, {B{\o}rge G} and Tangen, {Catherine M} and Southey, {Melissa C} and Alicja Wolk and Demetrius Albanes and Haiman, {Christopher A} and Travis, {Ruth C} and Stanford, {Janet L} and Mucci, {Lorelei A} and West, {Catharine M L} and Nielsen, {Sune F} and Kibel, {Adam S} and Olivier Cussenot and Berndt, {Sonja I} and Stella Koutros and S{\o}rensen, {Karina Dalsgaard} and Cezary Cybulski and Grindedal, {Eli Marie} and Park, {Jong Y} and Ingles, {Sue A} and Christiane Maier and Hamilton, {Robert J} and Rosenstein, {Barry S} and Ana Vega and {The Impact Study Steering Committee And Collaborators} and Manolis Kogevinas and Fredrik Wiklund and Penney, {Kathryn L} and Hermann Brenner and John, {Esther M} and Radka Kaneva and Logothetis, {Christopher J} and Neuhausen, {Susan L} and Ruyck, {Kim De} and Azad Razack and Newcomb, {Lisa F} and {Canary Pass Investigators} and Davor Lessel and Nawaid Usmani and Frank Claessens and Manuela Gago-Dominguez and Townsend, {Paul A} and Roobol, {Monique J} and {The Profile Study Steering Committee} and {The Practical Consortium} and Teixeira, {Manuel R}",

year = "2020",

month = nov,

day = "4",

doi = "10.3390/cancers12113254",

language = "English",

volume = "12",

pages = "1--17",

journal = "Cancers",

issn = "2072-6694",

publisher = "M D P I AG",

number = "11",

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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.

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 - Journal article

C2 - 33158149

VL - 12

SP - 1

EP - 17

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 11

M1 - 3254

ER -

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

Abstract

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