Abstract

Thyroid cancer is a malignant neoplasm that originates from follicular or parafollicular thyroid cells and is categorized as papillary (PTC), follicular (FTC), anaplastic (ATC) or medullary thyroid carcinoma (MTC). The alteration of the Rearranged during trasfection (RET) (proto-oncogene, a gene coding for a tyrosine-kinase receptor involved in the control of cell differentiation and proliferation, has been found to cause PTC and MTC. In particular, RET/PTC rearrangements and RET point mutations are related to PTC and MTC, respectively. Although RET/PTC rearrangements have been identified in both spontaneous and radiation-induced PTC, they occur more frequently in radiation-associated tumors. RET/PTC rearrangements have also been reported in follicular adenomas. Although controversial, correlations between RET/PTC rearrangements, especially RET/PTC3, and a more aggressive phenotype and a more advanced stage have been identified. Germline point mutations in the RET proto-oncogene are associated with nearly all cases of hereditary MTC, and a strict correlation between genotype and phenotype has been demonstrated. A large spectrum of RET point mutations has been reported to date. Somatic RET mutations, almost all of which are point mutations, have been described in approximately 40-50% of sporadic MTC cases. Although RET somatic mutations have been found in different codons, the M918T mutation in exon 16 is the most frequent. Detecting germline RET point mutations is a useful tool for identifying subjects who are clinically unaffected but who will develop the disease soon or late in their life, thus allowing presymptomatic treatment. From a clinical point of view, detecting RET somatic mutations in tumoral tissue is able to predict a poor outcome of the disease. In recent years, several drugs capable of inhibiting RET activity have been demonstrated to play an important role in the treatment of radiorefractory advanced thyroid carcinomas.

Highlights

  • Thyroid cancer is a malignant neoplasm that originates from follicular or parafollicular thyroid cells

  • 95% of malignant lesions are derived from thyroid follicular cells and are classified as papillary (PTC), follicular (FTC), or anaplastic (ATC) thyroid carcinoma [1]

  • All mutated genes are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway suggesting that activation of this signaling pathway is essential for tumor initiation and that the alteration of a single effector of the pathway is sufficient for cell transformation [6]

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Summary

Introduction

Thyroid cancer is a malignant neoplasm that originates from follicular or parafollicular thyroid cells. In the last 25 years, many studies have been conducted to identify the genetic alterations related to the pathogenesis of thyroid tumors. Most of these alterations affect genes coding for either some tyrosine kinases receptors, such as RET and NTRK1 or other proteins such as RAS and BRAF. The RET proto-oncogene encodes a transmembrane tyrosinekinase receptor involved in the control of cell differentiation and proliferation This receptor is characterized by an extracellular ligandbinding domain, including four cadherin-like repeats and a conserved cysteine-rich region; a transmembrane domain; and an intracellular domain containing two tyrosine-kinase subdomains that are involved in the dimerization of the receptor through disulfide bond formation [10]. J Genet Syndr Gene Ther 5: 214. doi:10.4172/21577412.1000214

Cancer Genetics
Non active ret receptor
Ret Point Mutations in Sporadic MTC
Substitution n
Clinical Relevance of Ret Point Mutations in MTC
Ret Oncogene Mutations and Target Therapy
Findings
Conclusions
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