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

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 M, 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, Doerk T, Du Bois A, Eccles D, Easton DT, Edwards RP, Eilber U, Ekici AB, Fasching P, Fridley BL, Gao YT, 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, Azmi MAN, 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 XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston L, Tangen IL, Teo SH, 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 YL, 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 (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B

Book Volume: 36

Pages Range: 1341-53

Journal Issue: 11

DOI: 10.1093/carcin/bgv138

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.

Authors with CRIS profile

Involved external institutions

Duke University United States (USA) (US) University of Cambridge United Kingdom (GB) University of Florida United States (USA) (US) University of Southern California (USC) United States (USA) (US) Xiamen University China (CN) Rutgers Cancer Institute of New Jersey United States (USA) (US) Memorial Sloan Kettering Cancer Center United States (USA) (US) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Dartmouth College United States (USA) (US) Princess Anne Hospital United Kingdom (GB) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) University of Kansas (KU) United States (USA) (US) Helsingin yliopisto / University of Helsinki Finland (FI) Peter MacCallum Cancer Centre Australia (AU) Mayo Clinic United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology Belarus (BY) Medical University of South Carolina (MUSC) United States (USA) (US) Oregon Health and Science University (OSHU) United States (USA) (US) University of Pittsburgh United States (USA) (US) University of Texas MD Anderson Cancer Center United States (USA) (US) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) Yale University United States (USA) (US) Princess Margaret Cancer Centre / Princess Margaret Hospital Canada (CA) Fred Hutchinson Cancer Research Center United States (USA) (US) Stanford University United States (USA) (US) Friedrich-Schiller-Universität Jena Germany (DE) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Vanderbilt University United States (USA) (US) University of Hawaii (U.H.) United States (USA) (US) Glasgow Royal Infirmary (GRI) United Kingdom (GB) The University of Melbourne Australia (AU) Texas Southern University (TSU) United States (USA) (US) Harvard University United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) British Columbia Cancer Agency Canada (CA) Cancer Council Victoria Australia (AU) University of New Mexico (UNM) / Universidad de Nuevo México United States (USA) (US) Shanghai Cancer Institute / 上海市肿瘤研究所 China (CN) University College London (UCL) United Kingdom (GB) Kliniken Essen-Mitte Germany (DE) Cancer Research Initiatives Foundation (CARIF) / Cancer Research Malaysia (CRM) Malaysia (MY) Danish Cancer Society Denmark (DK) Aichi Cancer Center Research Institute Japan (JP) Danish Cancer Society Research Center Denmark (DK) Radboud University Nijmegen Netherlands (NL) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Kyushu University / 九州大学 Japan (JP) Mount Sinai Hospital (MSH) Canada (CA) University of Glasgow United Kingdom (GB) Roswell Park Cancer Institute United States (USA) (US) Women's College Hospital Canada (CA) University of Copenhagen Denmark (DK) University of Malaya (UM) / Universiti Malaya Malaysia (MY) University of Michigan United States (USA) (US) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) Universität Ulm Germany (DE) University of Washington United States (USA) (US)

How to cite

APA:

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), 1341-53. https://doi.org/10.1093/carcin/bgv138

MLA:

Lawrenson, Kate, et al. "Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer." Carcinogenesis 36.11 (2015): 1341-53.

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