Ret Activation In Inherited And Sporadic Medullary Thyroid Carcinomas

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RET mutations in MEN2 syndromes

In 1991, genetic linkage analyses mapped putative loci for MEN2 syndrome to a small interval on chromosome 10q11.2 and few years later RET gene was identified as the susceptibility gene for these syndromes (Donis-Keller, H. et al., 1993; Mulligan, L. M. et al., 1993b; Carlson, K. M. et al., 1994; Eng, C. et al., 1994; Hofstra, R. M. et al., 1994). Unlike other cancer syndromes, which are associated with inactivation of tumor suppressor genes, MEN2 arises as a result of activating mutations of the RET gene. This was the first time that predisposition to a cancer syndrome was associated with the activation of an oncogene rather than inactivation of a tumor suppressor gene (reviewed in Frischauf, A. M., 1993).

Figure 5. Schematic diagram of the RET gene and RET protein showing the location of MEN2 mutations.

Germline point mutations of RET are responsible for the inheritance of all the autosomal dominant MEN2 cancer syndromes MEN2A, MEN2B and FMTC (Figure 5 and Table 3).

The correlation between the various RET mutations and the development of thyroid carcinomas has been proved in fibroblast (Santoro, M. et al., 1995; Borrello, M. G. et al., 1995) and in a variety of different transgenic models (Asai, N. et al., 1995; Michiels, F. M. et al., 1997; Reynolds, L. et al., 2001; Acton, D. S. et al., 2000).

RET in multiple endocrine neoplasia type 2A (MEN2A)

Missense mutations of the RET gene have been found in the constitutional DNA of virtually all MEN2A families. These mutations affect the cysteine-rich extracellular domain of RET, each converting a critical cysteine residue (Cys) to another aminoacid at codons 609, 611, 618, 620, (exon 10) or at codons 630, 634 (exon 11) (see references in Table 3). They account for 98% of all mutations associated with MEN2A; the most common mutation, accounting for over 80% of all mutations associated with MEN2A, affects codon 634 and converts this cysteine into an arginine in about half of cases. Rarer duplication/insertion mutations associated with MEN2A have been described in exon 11 (Hoppner, W. et al., 1997; Hoppner, W. et al., 1998) resulting in the insertion of three or four aminoacids including a cysteine residue within the cysteine-rich domain. De novo cases of MEN2A have been associated with two new germline mutations (at both codon 634 and 640) on the same RET allele (Tessitore, A. et al., 1999).

RET-MEN2A oncoproteins display constitutive kinase activity consequent to ligand-independent dimerization. It is postulated that the cysteine residues are normally involved in intramolecular disulfide bonds. The disruption of a Cys by mutation may render the partner Cys available for aberrant disulfide bonding with other mutant

Table 3. RET mutations in MEN2 syndromes and sMTC

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