Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC

Abstract

We have analysed 118 families with inherited medullary thyroid carcinoma (MTC) for mutations of the RET proto-oncogene. These included cases of multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial MTC (FMTC). Mutations at one of 5 cysteines in the extracellular domain were found in 97% of patients with MEN 2A and 86% with FMTC but not in MEN 2B patients or normal controls. 84% of the MEN2A mutations affected codon 634. MEN 2A patients with a Cys634 to Arg substitution had a greater risk of developing parathyroid disease than those with other codon 634 mutations. Our data show a strong correlation between disease phenotype and the nature and position of the RET mutation, suggesting that a simple, constitutive activation of the RET tyrosine kinase is unlikely to explain the events leading to MEN 2A and FMTC.

Mechanism of Activation of the ret Proto-oncogene by Multiple Endocrine Neoplasia 2A Mutations

“…Mutations identified in MEN 2A affected one of five cysteine residues (codons 609, 611, 618, and 620 in exon 10 and codon 634 in exon 11) encoded in the extracellular domain of the c-ret proto-oncogene (12). The most frequent mutation was cysteine to arginine at codon 634, and the second most frequent was cysteine to tyrosine at the same codon (Fig.…”

“…MEN 2B is distinguished from MEN 2A by a more complex phenotype including mucosal neuroma, hyperganglionosis of the gastrointestinal tract, and marfanoid habitus. MEN 2A and familial medullary thyroid carcinoma mutations always involve cysteine residues present in the extracellular domain of the c-ret proto-oncogene (4,12,13). These cysteine residues are conserved in both human and mouse c-ret proto-oncogenes, suggesting that they are important for normal conformation of the c-Ret protein (9,22,23).…”

Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma

“…In addition, we found that substitution of phenylalanine for tyrosine 905 present in the kinase domain abolished both transforming and autophosphorylation activities of low group Ret whereas it did not a ect the activities of high group Ret. (cysteines 609, 611, 618, 620, 630 and 634) in the extracellular domain of Ret (Mulligan et al, 1993(Mulligan et al, , 1994 Donis-Keller et al, 1993;Lips et al, 1994; Eng et al., 1996), whereas a point mutation (methionine 918?threonine, M918T) in the tyrosine kinase domain was detected in MEN 2B (Hofstra et al, 1994; Carlson et al, 1994). We and others demonstrated that MEN 2A, MEN 2B and FMTC mutations represent gain-of-function mutations (Santoro et al…”

“…Keywords: Ret; tyrosine kinase; MEN 2A; MEN 2B; FMTC Recent studies have established that germline mutations of the RET proto-oncogene are responsible for development of three dominantly inherited neoplastic disorders including multiple endocrine neoplasia (MEN) 2A, MEN 2B and familial medullary thyroid carcinoma (FMTC) (see Pasini et al, 1996 (cysteines 609, 611, 618, 620, 630 and 634) in the extracellular domain of Ret (Mulligan et al, 1993(Mulligan et al, , 1994Donis-Keller et al, 1993;Lips et al, 1994;Eng et al, 1996), whereas a point mutation (methionine 918?threonine, M918T) in the tyrosine kinase domain was detected in MEN 2B (Hofstra et al, 1994;Carlson et al, 1994). We and others demonstrated that MEN 2A, MEN 2B and FMTC mutations represent gain-of-function mutations (Santoro et al, 1995;Asai et al, 1995Asai et al, , 1996Borrelo et al, 1995;Iwashita et al, 1996;Rossel et al, 1997;Carlomagno et al, 1997;Ito et al, 1997).…”

Germline mutation of RET codon 883 in two cases of de novo MEN 2B

“…Ninety-eight percent of MEN 2A cases are caused by mutation of one of ®ve conserved cysteine residues in the extracellular domain of RET (C609, 611, 618, 620, 634) (Eng et al, 1996;Ponder and Smith, 1996;Eng and Mulligan, 1997;Mulligan et al, 1993Mulligan et al, , 1994. Receptor tyrosine kinases are activated by dimerisation induced by ligand binding to the extracellular domain (Pawson and Schlessinger, 1993).…”