Molecular basis of medullary thyroid carcinoma: the role of RET polymorphisms

Lucieli Ceolin, Débora R Siqueira, Mírian Romitti, Carla V Ferreira, Ana Luiza Maia, Lucieli Ceolin, Débora R Siqueira, Mírian Romitti, Carla V Ferreira, Ana Luiza Maia

Abstract

Medullary thyroid carcinoma is a rare malignant tumor originating in parafollicular C cells. It accounts for 5 to 8% of all thyroid cancers. MTC develops in either sporadic (75%) or hereditary form (25%). Genetic and molecular studies have demonstrated the involvement of the RET proto-oncogene in hereditary MTC and, less often, in its sporadic form. Although a strong genotype-phenotype correlation has been described, wide clinical heterogeneity is observed among families with the same RET mutation or even in carriers of the same kindred. In recent years, several single nucleotide polymorphisms of the RET gene have been described in the general population as well as in patients with MTC. Some studies have reported associations between the presence of polymorphisms and development or progression of MTC. Nonetheless, other studies failed to demonstrate any effect of the RET variants. Differences in the genetic background of distinct populations or methodological approaches have been suggested as potential reasons for the conflicting results. Here, we review current knowledge concerning the molecular pathogenesis of sporadic and hereditary MTC. In particular, we analyze the role of RET polymorphisms in the clinical presentation and prognosis of MTC based on the current literature.

Keywords: RET polymorphisms; medullary thyroid carcinoma; prognosis.

Figures

Figure 1
Figure 1
Schematic representation of the RET receptor. The extracellular region comprises the cadherin and cysteine rich domain. A single transmembrane region spans the cell membrane. Two tyrosine kinase domains (TK1 and TK2) are located in the intracellular region. The corresponding exons coding for the cysteine and thyrosine kinase domains are indicated.
Figure 2
Figure 2
Mechanisms of ligand-mediated RET activation. (A) In the cis model RET activation: the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFL) binds to membrane glycosylphosphatidylinositol-anchored GDNF-family coreceptors (GFRα). The activation leads to dimerization of RET and consequently activation of the intracellular signaling pathways; (B) In the trans model RET activation: the ligand binds to the soluble form of its coreceptor (GFRα) and the ligand-GFRα complex brings together two inactive RET monomers. Ligand-induced activation induces dimerization and tyrosine phosphorylation of the RET receptor with downstream activation of several signal transduction pathways.
Figure 3
Figure 3
Characterization of RET oncogenic activation in MEN2 inherited cancer syndromes. (A) MEN 2A RET mutation leaves an unpaired cysteine residue in a RET monomer to form an aberrant intermolecular disulfide bond with another mutated monomer. The two mutated RET molecules are constitutively dimerized and activated; (B) MEN 2B RET mutation activates tyrosines in the kinase domain and alters its substrate specificity leading to aberrant phosphorylation of substrates of RET receptor.

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