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

Publication ,  Journal Article
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 ...
Published in: Carcinogenesis
November 2015
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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.

Duke Scholars

Edwin Severin Iversen Jr.
Author Edwin Severin Iversen Jr. Statistical Science
Jeffrey R. Marks
Author Jeffrey R. Marks Surgery, Surgical Sciences
Andrew Berchuck
Author Andrew Berchuck Obstetrics and Gynecology, Gynecologic Oncology
Joellen Martha Schildkraut
Author Joellen Martha Schildkraut Family Medicine and Community Health, Prevention Research
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Published In

Carcinogenesis

DOI

10.1093/carcin/bgv138

EISSN

1460-2180

Publication Date

November 2015

Volume

36

Issue

11

Start / End Page

1341 / 1353

Location

England

Related Subject Headings

  • Risk Factors
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasms, Glandular and Epithelial
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Loci
 

Citation

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Lawrenson, K., Iversen, E. S., Tyrer, J., Weber, R. P., Concannon, P., Hazelett, D. J., … Schildkraut, J. M. (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
Lawrenson, Kate, Edwin S. Iversen, Jonathan Tyrer, Rachel Palmieri Weber, Patrick Concannon, Dennis J. Hazelett, Qiyuan Li, et al. “Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.” Carcinogenesis 36, no. 11 (November 2015): 1341–53. https://doi.org/10.1093/carcin/bgv138.
Lawrenson K, Iversen ES, Tyrer J, Weber RP, Concannon P, Hazelett DJ, et al. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. Carcinogenesis. 2015 Nov;36(11):1341–53.
Lawrenson, Kate, et al. “Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.” Carcinogenesis, vol. 36, no. 11, Nov. 2015, pp. 1341–53. Pubmed, doi: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, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, 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, Giles GG, Glasspool R, Goode EL, Goodman MT, Gronwald J, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Hogdall E, Hogdall C, Hosono S, Jakubowska A, Paul J, Jensen A, Karlan BY, Kjaer SK, Kelemen LE, Kellar M, Kelley JL, Kiemeney LA, Krakstad C, Lambrechts D, Lambrechts S, Le ND, Lee AW, Cannioto R, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LFAG, Matsuo K, McGuire V, McLaughlin JR, Nevanlinna H, McNeish I, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Noor Azmi MA, Odunsi K, Olson SH, Orlow I, Orsulic S, Pearce CL, Pejovic T, Pelttari LM, Permuth-Wey J, Phelan CM, Pike MC, Poole EM, Ramus SJ, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Budzilowska A, Sellers TA, Shu X-O, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston L, Tangen IL, Teo S-H, Terry KL, Thompson PJ, Timorek A, Tworoger SS, Van Nieuwenhuysen E, Vergote I, Vierkant RA, Wang-Gohrke S, Walsh C, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo Y-L, Wu X, Wu AH, Yang H, Zheng W, Ziogas A, Coetzee GA, Freedman ML, Monteiro ANA, Moes-Sosnowska J, Kupryjanczyk J, Pharoah PD, Gayther SA, Schildkraut JM. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. Carcinogenesis. 2015 Nov;36(11):1341–1353.
Journal cover image

Published In

Carcinogenesis

DOI

10.1093/carcin/bgv138

EISSN

1460-2180

Publication Date

November 2015

Volume

36

Issue

11

Start / End Page

1341 / 1353

Location

England

Related Subject Headings

  • Risk Factors
  • Quantitative Trait Loci
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasms, Glandular and Epithelial
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Loci