A targeted genetic association study of epithelial ovarian cancer susceptibility.
BACKGROUND:Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci. RESULTS:At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p <5x10(-8)), nor were any significant after Bonferroni correction for 17,000 variants (p< 3x10-6). METHODS:A customized genotyping array was used to assess over 17,000 variants in coding, non-coding, regulatory, and known susceptibility regions in 4,973 EOC cases and 5,640 controls from 13 independent studies. Susceptibility for EOC overall and for select histotypes was evaluated using logistic regression adjusted for age, study site, and population substructure. CONCLUSION:Given the novel variants identified within the 2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13 regions, larger follow-up genotyping studies, using imputation where necessary, are needed for fine-mapping and confirmation of low frequency variants that fall below statistical significance.
Earp, M; Winham, SJ; Larson, N; Permuth, JB; Sicotte, H; Chien, J; Anton-Culver, H; Bandera, EV; Berchuck, A; Cook, LS; Cramer, D; Doherty, JA; Goodman, MT; Levine, DA; Monteiro, ANA; Ness, RB; Pearce, CL; Rossing, MA; Tworoger, SS; Wentzensen, N; Bisogna, M; Brinton, L; Brooks-Wilson, A; Carney, ME; Cunningham, JM; Edwards, RP; Fogarty, ZC; Iversen, ES; Kraft, P; Larson, MC; Le, ND; Lin, H-Y; Lissowska, J; Modugno, F; Moysich, KB; Olson, SH; Pike, MC; Poole, EM; Rider, DN; Terry, KL; Thompson, PJ; van den Berg, D; Vierkant, RA; Vitonis, AF; Wilkens, LR; Wu, AH; Yang, HP; Ziogas, A; Phelan, CM; Schildkraut, JM; Chen, YA; Sellers, TA; Fridley, BL; Goode, EL
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