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

Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group

Research output: Contribution to journalArticle

16 Citations (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.

Original languageEnglish (US)
Pages (from-to)1341-1353
Number of pages13
JournalCarcinogenesis
Volume36
Issue number11
DOIs
StatePublished - Nov 1 2015

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Single Nucleotide Polymorphism
Genes
Genotype
Genome
Fallopian Tubes
Atlases
Genome-Wide Association Study
Ovarian epithelial cancer
DNA Repair
Transcription Factors
Odds Ratio
Binding Sites
Gene Expression
DNA
Neoplasms

ASJC Scopus subject areas

  • Cancer Research

Cite this

Australian Cancer Study (Ovarian Cancer), & Australian Ovarian Cancer Study Group (2015). Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. Carcinogenesis, 36(11), 1341-1353. https://doi.org/10.1093/carcin/bgv138

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. / Australian Cancer Study (Ovarian Cancer); Australian Ovarian Cancer Study Group.

In: Carcinogenesis, Vol. 36, No. 11, 01.11.2015, p. 1341-1353.

Research output: Contribution to journalArticle

Australian Cancer Study (Ovarian Cancer) & Australian Ovarian Cancer Study Group 2015, 'Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer', Carcinogenesis, vol. 36, no. 11, pp. 1341-1353. https://doi.org/10.1093/carcin/bgv138
Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. Carcinogenesis. 2015 Nov 1;36(11):1341-1353. https://doi.org/10.1093/carcin/bgv138
Australian Cancer Study (Ovarian Cancer) ; Australian Ovarian Cancer Study Group. / Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. In: Carcinogenesis. 2015 ; Vol. 36, No. 11. pp. 1341-1353.
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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.",
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AU - Australian Cancer Study (Ovarian Cancer)

AU - Australian Ovarian Cancer Study Group

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

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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 - Cunningham, Julie M

AU - Dennis, Joe

AU - Dicks, Ed

AU - Doherty, Jennifer A.

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AU - Fridley, Brooke L.

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AU - Gentry-Maharaj, Aleksandra

AU - Giles, Graham G.

AU - Goode, Ellen L

PY - 2015/11/1

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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.

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