Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Kate Lawrenson; Edwin S Iversen; Jonathan Tyrer; Rachel Palmieri Weber; Patrick Concannon; Dennis J Hazelett; Qiyuan Li; Jeffrey R Marks; Andrew Berchuck; Janet M Lee; Katja K H Aben; Hoda Anton-Culver; Natalia Antonenkova; Elisa V Bandera; Yukie Bean; Matthias W Beckmann; Maria Bisogna; Line Bjorge; Natalia Bogdanova; Louise A Brinton; Angela Brooks-Wilson; Fiona Bruinsma; Ralf Butzow; Ian G Campbell; Karen Carty; Jenny Chang-Claude; Georgia Chenevix-Trench; Ann Chen; Zhihua Chen; Linda S Cook; Daniel W Cramer; Julie M Cunningham; Cezary Cybulski; Joanna Plisiecka-Halasa; Joe Dennis; Ed Dicks; Jennifer A Doherty; Thilo Dörk; Andreas du Bois; Diana Eccles; Douglas T Easton; Robert P Edwards; Ursula Eilber; Arif B Ekici; Peter A Fasching; Brooke L Fridley; Yu-Tang Gao; Aleksandra Gentry-Maharaj; Claus Hogdall; Susanne Kruger Kjaer; Australian Cancer Study (Ovarian Cancer)

doi:10.1093/carcin/bgv138

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Kate Lawrenson, Edwin S Iversen, Jonathan Tyrer, Rachel Palmieri Weber, Patrick Concannon, Dennis J Hazelett, Qiyuan Li, Jeffrey R Marks, Andrew Berchuck, Janet M Lee, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Elisa V Bandera, Yukie Bean, Matthias W Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A BrintonAngela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Georgia Chenevix-Trench, Ann Chen, Zhihua Chen, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Joanna Plisiecka-Halasa, Joe Dennis, Ed Dicks, Jennifer A Doherty, Thilo Dörk, Andreas du Bois, Diana Eccles, Douglas T Easton, Robert P Edwards, Ursula Eilber, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Claus Hogdall, Susanne Kruger Kjaer, Australian Cancer Study (Ovarian Cancer)

Institut for Klinisk Medicin

21 Citationer (Scopus)

Abstract

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

Originalsprog	Engelsk
Tidsskrift	Carcinogenesis
Vol/bind	36
Udgave nummer	11
Sider (fra-til)	1341-53
Antal sider	13
ISSN	0143-3334
DOI	https://doi.org/10.1093/carcin/bgv138
Status	Udgivet - 1 nov. 2015

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10.1093/carcin/bgv138

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Lawrenson, K., Iversen, E. S., Tyrer, J., Weber, R. P., Concannon, P., Hazelett, D. J., Li, Q., Marks, J. R., Berchuck, A., Lee, J. M., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Bandera, E. V., Bean, Y., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., ... Australian Cancer Study (Ovarian Cancer) (2015). Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. Carcinogenesis, 36(11), 1341-53. https://doi.org/10.1093/carcin/bgv138

Lawrenson, K, Iversen, ES, Tyrer, J, Weber, RP, Concannon, P, Hazelett, DJ, Li, Q, Marks, JR, Berchuck, A, Lee, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bandera, EV, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Plisiecka-Halasa, J, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, du Bois, A, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Hogdall, C , Kjaer, SK & Australian Cancer Study (Ovarian Cancer) 2015, 'Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer', Carcinogenesis, bind 36, nr. 11, s. 1341-53. https://doi.org/10.1093/carcin/bgv138

@article{29451e19d61247129c64bca957e564bd,

title = "Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer",

abstract = "Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.",

keywords = "Case-Control Studies, Checkpoint Kinase 2, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors",

author = "Kate Lawrenson and Iversen, {Edwin S} and Jonathan Tyrer and Weber, {Rachel Palmieri} and Patrick Concannon and Hazelett, {Dennis J} and Qiyuan Li and Marks, {Jeffrey R} and Andrew Berchuck and Lee, {Janet M} and Aben, {Katja K H} and Hoda Anton-Culver and Natalia Antonenkova and Bandera, {Elisa V} and Yukie Bean and Beckmann, {Matthias W} and Maria Bisogna and Line Bjorge and Natalia Bogdanova and Brinton, {Louise A} and Angela Brooks-Wilson and Fiona Bruinsma and Ralf Butzow and Campbell, {Ian G} and Karen Carty and Jenny Chang-Claude and Georgia Chenevix-Trench and Ann Chen and Zhihua Chen and Cook, {Linda S} and Cramer, {Daniel W} and Cunningham, {Julie M} and Cezary Cybulski and Joanna Plisiecka-Halasa and Joe Dennis and Ed Dicks and Doherty, {Jennifer A} and Thilo D{\"o}rk and {du Bois}, Andreas and Diana Eccles and Easton, {Douglas T} and Edwards, {Robert P} and Ursula Eilber and Ekici, {Arif B} and Fasching, {Peter A} and Fridley, {Brooke L} and Yu-Tang Gao and Aleksandra Gentry-Maharaj and Claus Hogdall and Kjaer, {Susanne Kruger} and {Australian Cancer Study (Ovarian Cancer)}",

year = "2015",

month = nov,

day = "1",

doi = "10.1093/carcin/bgv138",

language = "English",

volume = "36",

pages = "1341--53",

journal = "Carcinogenesis",

issn = "0143-3334",

publisher = "Oxford University Press",

number = "11",

}

TY - JOUR

T1 - Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

AU - Lawrenson, Kate

AU - Iversen, Edwin S

AU - Tyrer, Jonathan

AU - Weber, Rachel Palmieri

AU - Concannon, Patrick

AU - Hazelett, Dennis J

AU - Li, Qiyuan

AU - Marks, Jeffrey R

AU - Berchuck, Andrew

AU - Lee, Janet M

AU - Aben, Katja K H

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia

AU - Bandera, Elisa V

AU - Bean, Yukie

AU - Beckmann, Matthias W

AU - Bisogna, Maria

AU - Bjorge, Line

AU - Bogdanova, Natalia

AU - Brinton, Louise A

AU - Brooks-Wilson, Angela

AU - Bruinsma, Fiona

AU - Butzow, Ralf

AU - Campbell, Ian G

AU - Carty, Karen

AU - Chang-Claude, Jenny

AU - Chenevix-Trench, Georgia

AU - Chen, Ann

AU - Chen, Zhihua

AU - Cook, Linda S

AU - Cramer, Daniel W

AU - Cunningham, Julie M

AU - Cybulski, Cezary

AU - Plisiecka-Halasa, Joanna

AU - Dennis, Joe

AU - Dicks, Ed

AU - Doherty, Jennifer A

AU - Dörk, Thilo

AU - du Bois, Andreas

AU - Eccles, Diana

AU - Easton, Douglas T

AU - Edwards, Robert P

AU - Eilber, Ursula

AU - Ekici, Arif B

AU - Fasching, Peter A

AU - Fridley, Brooke L

AU - Gao, Yu-Tang

AU - Gentry-Maharaj, Aleksandra

AU - Hogdall, Claus

AU - Kjaer, Susanne Kruger

AU - Australian Cancer Study (Ovarian Cancer)

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

AB - Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.

KW - Case-Control Studies

KW - Checkpoint Kinase 2

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Neoplasms, Glandular and Epithelial

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Risk Factors

U2 - 10.1093/carcin/bgv138

DO - 10.1093/carcin/bgv138

M3 - Journal article

C2 - 26424751

SN - 0143-3334

VL - 36

SP - 1341

EP - 1353

JO - Carcinogenesis

JF - Carcinogenesis

IS - 11

ER -

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

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