Polymorphisms Within the Proto-Oncogene and Risk of Sporadic Medullary Thyroid Carcinoma.

Sporadic medullary thyroid carcinoma (sMTC) is an uncommon neoplasia arising from the calcitonin-producing parafollicular cells of the thyroid. Previous studies evaluated whether single nucleotide polymorphisms (SNPs) within (a pivotal proto-oncogene for this disease) are associated with the risk for developing sMTC, but the results are inconclusive. In this work, we evaluated the association of -SNPs c.74-126G>T (rs2565206), p.Gly691Ser (rs1799939, G>A), p.Leu769 = (rs1800861, G>T), p.Ser836 = (rs1800862, C>T), and p.Ser904 = (rs1800863, C>G) (listed in the order of their chromosomal location) with sMTC. This is one of the largest casecontrol association studies carried out on sMTC, including 585 sMTC cases (negative for germline mutations within ), 1529 patients affected by sporadic nonmedullary thyroid carcinoma (sNMTC), and 989 healthy controls, from central and southern Italy and collected in the period 2000-2017. sNMTC patients showed similar genotype and allele frequencies compared with healthy controls. On the other hand, among sMTC patients, the T-allele of p.Leu769 = was less frequent (OR = 0.70 [CI 0.58-0.84],  = 1.9 × 10) and rare homozygotes TT showed an OR = 0.32 ([CI 0.17-0.60],  = 2.3 × 10). Moreover, a statistically significant excess of the haplotype 2 (characterized by the alleles T-G-G-C-C of the listed SNPs) was observed ( = 3.9 × 10). The SNPs were not associated with the expression of mRNA, that is, they did not exert an effect in as quantitative trait locus (cis-eQTL). However, a strong eQTL association was found for p.Leu769 = and the neighboring gene ( = 9.3 × 10; effect-size = -0.65), whose function in cancer is unknown. This study shows that specific haplotypes, in particular haplotype 2 and the T-allele of p.Leu769 = , are associated with a reduced risk of sMTC in Italians.