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