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 Tarumi 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, Y. Ann Chen, Zhihua Chen, Linda S. Cook, Daniel W. Cramer, Julie M. Cunningham, Cezary Cybulski, Joanna Plisiecka-Halasa, Joe Dennis, Ed Dicks, Jennifer Anne Doherty, Thilo Dörk, Andreas Du Bois, Diana M Eccles, Douglas T. Easton, Robert P. Edwards, Ursula Eilber, Arif B Ekici, Peter A. Fasching, Brooke L. Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind M Glasspool, Ellen L Goode, Marc T Goodman, Jacek Gronwald, Philipp Harter, Hanis Nazihah Hasmad, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Estrid Hogdall, Claus Hogdall, Satoyo Hosono, Anna Jakubowska, James Paul, Allan Jensen, Beth Y. Karlan, Susanne Kruger Ruger Kjaer, Linda E. Kelemen, Melissa Kellar, Joseph L. Kelley, Lambertus A. Kiemeney, Camilla Krakstad, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Alice W Lee, Rikki Cannioto, Arto Leminen, Jenny Lester, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Heli Nevanlinna, Iain A McNeish, Usha N Menon, Francesmary Modugno, Kirsten B Moysich, Steven A Narod, Lotte Nedergaard, Roberta B Ness, Mat Adenan Noor Azmi, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Jennifer Permuth-Wey, Catherine M Phelan, Malcolm C Pike, Elizabeth M Poole, Susan J Ramus, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga Birgitte Salvesen, Agnieszka Budzilowska, Thomas A Sellers, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Lara E Sucheston, Ingvild L Tangen, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Agnieszka Timorek, Shelley S Tworoger, Els Van Nieuwenhuysen, Ignace Vergote, Robert A Vierkant, Shan Wang-Gohrke, Christine S Walsh, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R. Wilkens, Yin Ling Woo, Xifeng Wu, Anna H Wu, Hannah P Yang, Wei Zheng, Argyrios Ziogas, Gerhard A. Coetzee, Matthew L Freedman, Alvaro N.A. Monteiro, Joanna Moes-Sosnowska, Jolanta Kupryjanczyk, Paul D P Pharoah, Simon A Gayther, Joellen M Schildkraut, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group

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21 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
Pages (from-to)1341-1353
Number of pages13
JournalCarcinogenesis
Volume36
Issue number11
DOIs
Publication statusPublished - 1 Nov 2015
Externally publishedYes

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