Abstract 4638: Fine mapping of two GWAS at 9q22 and 14q13 associated with differentiated thyroid cancer risk

Abstract

Abstract Context: Incidence of differentiated thyroid carcinoma (DTC) varies considerably between countries and ethnic groups. High incidence rates have been reported in Pacific islands, especially in Melanesian women of New Caledonia (NC). DTC was reported as the only cancer for which the contribution of inherited genetic factors exceeds that of environmental factors. Recent genome-wide associations studies (GWAS) have identified several susceptibility loci, the most robust associations were reported for SNPs in chromosomes 9q22 (rs965513 and rs186727) and 14q13 (rs942289 and rs116909734). It remains unclear whether these 4 SNPs represent independent signals of association or if there are other independent signals within each locus. We aimed to replicate the 4 previously identified SNPs at 9q22 and 14q13 in a population of European descent and in the high risk population of Melanesians in NC. We also sought to determine if there are other SNPs with stronger association and if multiple SNPs are independently associated to DTC within each locus. Methods: We included subjects from 2 case-control studies, conducted in Metropolitan France and in New Caledonia. We genotyped and imputed 81 SNPs at 9q22 and 561 SNPs at 14q13 in 625 cases and 776 controls of European ancestry and 244 cases and 189 controls of Melanesian ethnicity. We performed logistic regression using the log-additive model and we conducted conditional analysis to identify independent markers of DTC. Results: At locus 9q22, among Europeans, we replicated the association of DTC with rs965513 (OR = 1.52, p = 5.9 × 10-6) and rs1867277 (OR = 1.38, p = 2.5 × 10-4). No other SNP was significantly associated with DTC after conditioning on rs965513. In Melanesians, ORs for rs965513 and rs1867277 were similar to those observed in Europeans, but no variant was significantly associated with DTC. At locus 14q13, we replicated the SNPs rs944289 (OR = 0.41, p = 4.7 × 10-4) and rs116909374 (OR = 1.97, p = 3.3 × 10-3) in Europeans, and conditional analysis revealed a third independent signal at rs999460. In Melanesians, we replicated the association with rs944289 (OR = 0.74, p = 1.1 × 10-3) but not with rs11699374. The most significant signal was observed for an independent SNP rs1755774 (OR = 0.57, p = 1.6 × 10-5). This variant was also associated with DTC in Europeans (OR = 0.70, p = 7.3 × 10-3). Interestingly, this variant is located in a region containing an uncharacterized lincRNA, which is abundantly expressed in thyroid tissue. Examination of the observed associations of DTC with SNPs cannot account for the striking difference in incidence rates between Europeans and Melanesians. Conclusion: We confirmed the previously reported associations of DTC with SNPs at locus 9q22 and 14q13. No additional other signal was observed at locus 9q22. At locus 14q13, we identified new interesting susceptibility SNPs in both ethnic groups. SNPs at 9q22 and 14q13 cannot explain the very high incidence of DTC in Melanesians compared to Europeans. Citation Format: catherine TCHEANDJIEU, Fabienne LESUEUR, Marie Sanchez, Therese TRUONG, Pascal GUENEL. Fine mapping of two GWAS at 9q22 and 14q13 associated with differentiated thyroid cancer risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4638. doi:10.1158/1538-7445.AM2015-4638