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The predisposing gene for inherited MTC was
localized in centromeric chromosome 10 by
genetic linkage analysis in 1987 3,4 and germline
mutations of the ret proto-oncogene were identified
in 1993 in MEN-2A, FMTC and MEN-2B 5,6,7.
The ret gene is a 21 exon gene that encodes a tyrosine kinase receptor. This membrane-associated receptor is characterized by a cadherin-like region in the extracellular domain, a cysteine-rich region immediately external to the membrane, and an intracellular tyrosine kinase domain. Mutations causing MEN-2A affect the cysteine-rich extracellular domain, each converting a cysteine to another amino acid, in codon 634 (exon 11) or in codons 609, 611, 618, and 620 (exon 10). These mutations account for 98 % of all mutations associated with MEN-2A; the most common mutation, accounting for over 80 % of all mutations associated with MEN-2A, affects codon 634. In about half of FMTC kindreds, mutations affect codons in exon 10, and mainly codons 618 and 620. In a limited number of families, mutations affect exon 11 (codons 630, 631, and 634). In the other half of FMTC kindreds, mutations may affect codons 768, 790, 791 (exon 13), 804, 844 (exon 14) and 891 (exon 15) in the intra-cellular domain of the gene 8–12. Over 95 % of kindreds with MEN-2A and FMTC have a mutation of one of these codons. Finally, rare mutations have recently been reported, such as a 9-base pair duplication in exon 8 in a FMTC family 13 . The rare families in which no mutation of the ret proto-oncogene has been identified, usually comprise only few affected members. De novo mutations (ie, germline mutation that does not exist in parents) have been found in 4 % to 10 % of index cases with MEN-2A and FMTC and are located on the allele inherited from the patient’s father 14. A single mutation converting a methionine into a threonine at codon 918 (exon 16) has been identified in approximately 95 % of patients with MEN-2B 6,15. It is frequently a de novo mutation that is located on the allele inherited from the patient’s father 16 . Other rare intracellular mutations associated with MEN-2B involve codon 883 (exon 15)17. There is a close relationship between genotype and phenotype. The risk of pheochromocytoma is about 50 % in subjects with a codon 634 mutation and about 10 % in subjects with a mutation in exon 10. Pheochromocytoma has been reported in rare patients with mutations in exons 13 (codons 790, 791) or 14 (codon 804). All MEN-2A families with parathyroid neoplasia or cutaneous lichen amyloidosis syndrome have a codon 634 mutation 11,18. Families with MEN-2A syndrome and Hirschsprung’s disease have a mutation in codons 609, 618 or 620 19. When compared to subjects with mutations in exons 10 or 11, clinical MTC occurs later in life and has a less aggressive course in subjects with mutations in exons 13 or 14 9. In contrast, MTC occurs earlier in life and has a more aggressive course in MEN-2B syndrome. These clinical features are in accordance with in vitro studies 20. Point mutations of the ret protooncogene result in an unregulated dominant activation of the tyrosine kinase receptor. Both extracellular cysteine (codon 634) and the intracellular tyrosine kinase (codon 918) mutations transform NIH 3T3 cells. Transgenic mice, in which the expression of a ret gene with a codon 634 mutation is targeted to the C cells by the calcitonin promoter, develop C cell hyperplasia and MTC 21. Finally, these mutations have been found in sporadic MTC’s. |
