Modifying impact of RET gene haplotypes on medullary thyroid carcinoma clinical course

Abstract

The clinical course of medullary thyroid carcinoma (MTC) associated with the MEN2A syndrome as well as of sporadic MTC shows considerable heterogeneity. The disease picture varies not only between the same <i>RET</i> proto-oncogene mutation carriers but also among sporadic MTC patients with no <i>RET</i> germinal mutations, which suggests the involvement of additional modulators of the disease. However, genetic factors responsible for this heterogeneity of the MTC clinical course still remain unknown. The aim of this study was to determine if polymorphic variants or specific haplotypes of the <i>RET</i> gene may modify the MTC clinical course. We genotyped the following <i>loci:</i> c.73+9277T>C, c.135G>A, c.1296A>G, c.2071G>A, c.2307T>C, c.2508C>T and c.2712C>G in 142 MTC patients and controls. We demonstrated considerable differences in the genotypes distribution within c.73+9277T>C, c.135G>A and c.2307T>C <i>loci</i> Our results show that the c.73+9277T variant associated with a decreased activity of the MCS+9.7 <i>RET</i> enhancer is rare in hereditary MTC patients with primary hyperparathyroidism, and thus, may influence the MTC clinical picture. The decreased activity of the <i>RET</i> promoter enhancer reduces <i>RET</i> expression level and may counterbalance the activating mutation in this gene. Frequent co-occurrence of the c.73+9277T allele with p.E768D, p.Y791F, p.V804M or p.R844Q <i>RET</i> mutations may be associated with their attenuation and milder clinical picture of the disease. Haplotypes analysis showed that C-G-A-G-T-(C)-C (c.73+9277T>C - c.135G>A - c.1296A>G - c.2071G>A - c.2307T>G - (c.2508C>T) - c.2712C>G) alleles combination predisposes to pheochromocytomas and primary hyperparathyroidism. We consider that <i>RET</i> haplotypes defining may become an auxiliary diagnostic tool in MTC patients.