Genetic risk association of CDKN1A and RET gene SNPs with medullary thyroid carcinoma: Results from the largest MTC cohort and meta-analysis

Abstract

Background: Medullary thyroid carcinoma (MTC) is a rare subtype of thyroid cancer. Other than gain-of-function RET mutations, no other genetic, lifestyle or environmental risk associations have been established for MTC. Several case-control studies and meta-analysis have examined the risk association of different SNPs with MTC in different populations but with contradictory or inconclusive results. Methods: In a large cohort of 438 Indian MTC cases and 489 gender and ethnicity matched healthy controls from 1000 genome project, a comprehensive risk association of 13 SNPs of three pathways—detoxification, cell cycle regulation and RET was performed along with meta-analysis of RET SNPs. Results: Multivariate logistic regression analysis identified a protective risk association of CDKN1ASer31Arg SNP with both hereditary (OR 0.26; 95% confidence interval [CI] 0.13-0.55; P '.001) and sporadic MTC (OR 0.53; 95% CI 0.36-0.78; P =.001). An increased risk association was identified for NAT2Y94Y SNP (OR 1.62, 95% CI 1.17-2.25, P =.004) and CDKN2A3′UTR SNP (OR 1.89, 95% CI 1.19-2.98, P =.006) with sporadic MTC and RET S904S with hereditary MTC (OR 2.82, 95% CI 1.64-4.86, P '.001). Meta-analysis of RET SNPs including our cohort identified increased risk association of all four RET SNPs with MTC. Conclusion: In this largest SNP risk association study for MTC and the only risk association study of the 13 most commonly studied MTC associated SNPs in a single cohort of this rare cancer, a significant protective risk association of CDKN1ASer31Arg SNP with MTC was shown for the first time. Meta-analysis identified significant risk association of all four RET SNPs, not observed in previous meta-analysis.