Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.
Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
Earp, MA; Kelemen, LE; Magliocco, AM; Swenerton, KD; Chenevix-Trench, G; Australian Cancer Study, ; Australian Ovarian Cancer Study Group, ; Lu, Y; Hein, A; Ekici, AB; Beckmann, MW; Fasching, PA; Lambrechts, D; Despierre, E; Vergote, I; Lambrechts, S; Doherty, JA; Rossing, MA; Chang-Claude, J; Rudolph, A; Friel, G; Moysich, KB; Odunsi, K; Sucheston-Campbell, L; Lurie, G; Goodman, MT; Carney, ME; Thompson, PJ; Runnebaum, IB; Dürst, M; Hillemanns, P; Dörk, T; Antonenkova, N; Bogdanova, N; Leminen, A; Nevanlinna, H; Pelttari, LM; Butzow, R; Bunker, CH; Modugno, F; Edwards, RP; Ness, RB; du Bois, A; Heitz, F; Schwaab, I; Harter, P; Karlan, BY; Walsh, C; Lester, J; Jensen, A; Kjær, SK; Høgdall, CK; Høgdall, E; Lundvall, L; Sellers, TA; Fridley, BL; Goode, EL; Cunningham, JM; Vierkant, RA; Giles, GG; Baglietto, L; Severi, G; Southey, MC; Liang, D; Wu, X; Lu, K; Hildebrandt, MAT; Levine, DA; Bisogna, M; Schildkraut, JM; Iversen, ES; Weber, RP; Berchuck, A; Cramer, DW; Terry, KL; Poole, EM; Tworoger, SS; Bandera, EV; Chandran, U; Orlow, I; Olson, SH; Wik, E; Salvesen, HB; Bjorge, L; Halle, MK; van Altena, AM; Aben, KKH; Kiemeney, LA; Massuger, LFAG; Pejovic, T; Bean, YT; Cybulski, C; Gronwald, J; Lubinski, J; Wentzensen, N; Brinton, LA; Lissowska, J; Garcia-Closas, M; Dicks, E; Dennis, J; Easton, DF; Song, H; Tyrer, JP; Pharoah, PDP; Eccles, D; Campbell, IG; Whittemore, AS; McGuire, V; Sieh, W; Rothstein, JH; Flanagan, JM; Paul, J; Brown, R; Phelan, CM; Risch, HA; McLaughlin, JR; Narod, SA; Ziogas, A; Anton-Culver, H; Gentry-Maharaj, A; Menon, U; Gayther, SA; Ramus, SJ; Wu, AH; Pearce, CL; Pike, MC; Dansonka-Mieszkowska, A; Rzepecka, IK; Szafron, LM; Kupryjanczyk, J; Cook, LS; Le, ND; Brooks-Wilson, A; Ovarian Cancer Association Consortium,
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