Polymorphisms within the RET proto-oncogene and risk of sporadic medullary thyroid carcinoma

BACKGROUND: 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 RET (a pivotal proto-oncogene for this disease) are associated with the risk for developing sMTC, but the results are inconclusive. METHODS: In this work we evaluated the association of RET-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 case-control association studies carried out on sMTC including 585 sMTC cases (negative for germline mutations within RET), 1529 patients affected by sporadic non-medullary thyroid carcinoma (sNMTC), and 989 healthy controls, from central and southern Italy and collected in the period 2000-2017. RESULTS: sNMTC patients showed similar genotype and allele frequencies compared to healthy controls. On the other hand, among sMTC patients, the T-allele of p.Leu769= was less frequent (OR=0.70; 95% CI=0.58-0.84; P-value=1.9x10-4) and rare homozygotes TT showed an OR=0.32 (95% CI=0.17-0.60; P-value=2.3x10-4). Moreover, a statistically significant excess of the haplotype 2 (characterized by the alleles T-G-G-C-C of the listed SNPs ) was observed (P-value=3.9x10-3). The SNPs were not associated with the expression of RET mRNA, i.e. they did not work as cis-expression Quantitative Trait Loci (cis-eQTL). However, a strong eQTL-association was found for p.Leu769= and the neighboring gene CSGALNACT2 (P-value=9.3x10-50; effect-size=-0.65), whose function in cancer is unknown. CONCLUSIONS: The present study showed that specific RET-haplotypes, in particular haplotype 2 and the T-allele of p.Leu769=, are associated with a reduced risk of sMTC in Italians.