Medullary carcinoma of the thyroid (Medullar Thyroid Cancer – MTC) occurs mostly in the sporadic form (75?%), and less frequently in the familial form (25?%). The cause of both MTC and MEN 2 syndromes are activating ("gain of function") spot mutations of RET proto-oncogene. RET proto-oncogene is found on 10q11.2, contains 20 exons and its length is 55 kilobytes (Pasini et al., 1995). RET encodes a transmembrane tyrosine kinase receptor which is important in the differentiation and development of tissues derived from the neural crest. In sporadic forms of MTC, mutations occur somatically (Met918Thr is frequent), i.e. only in the tumor tissue. In hereditary forms, germline mutations occur. The familial form is inherited in an autosomal dominant way and has three variants:
Familial MTC (FMTC) is the least aggressive form of MTC and represents 1-9?% of all MTC families. Other endocrine neoplasia are not present. FMTC is primarily associated with mutations of the RET gene in exon 10 (codons 609, 611, 618 and 620), in exon 11, exon 13 (codon 768), in exon 14 (codon 804) and in exon 15.
MEN 2A syndrome includes 15 to 23?% of all MTC families. MTC often occurs also simultaneously together with pheochromocytoma and primary hyperparathyroidism. MEN 2A is mainly associated with mutations of the RET gene in exon 10 (codons 609, 611, 618 and 620) and in exon 11 (codon 634).
MEN 2B syndrome is the most aggressive form of MTC and includes roughly 1?% of all MTC families. Pheochromocytoma, rarely hyperparathyroidism also often occurs simultaneously together with MTC. MEN 2B is mainly associated with mutations in RET gene in exon 16 (codon 918, > 95%) and in exon 15 (codon 883).
Germinal "loss of function" of RET mutations are the most common cause of Hirschsprung's disease (HSCR), in which the absence of innervations of certain sections of the intestine occurs.
Detection of mutations in the entire coding region of the RET gene is performed using an accredited method PCR (with primers amplificating all 20 exons, including exon-intron connections) and direct sequencing.
RET is the only gene whose mutations are responsible for MEN 2 phenotype. Mutations in the RET gene were found in 98% of individuals with MEN2A phenotype, in over 98% of individuals with MEN 2B phenotype and in about 95% of families with FMTC phenotype.
Sequencing analysis of the coding exons and exon-intron connections captures about 92% of mutations in RET gene listed in a publicly available version of database of mutations HGMD (The Human Gene Mutation Database).
Analytical sensitivity and specificity of sequencing: 99%.
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