Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours

Abstract

The susceptibility loci for the three multiple endocrine neoplasia (MEN) type 2 syndromes have been mapped to the region of chromosome 10q11.2 containing the RET proto-oncogene, which codes for a receptor tyrosine kinase. The majority of MEN 2A and familial medullary thyroid carcinoma results from missense mutations within one of five cysteine codons in the extracellular domain of the RET proto-oncogene. We now report a missense mutation, resulting in the substitution of a threonine for a methionine at codon 918 in the tyrosine kinase catalytic domain, in the germline of 26 of 28 apparently distinct families with MEN 2B. DNA from five of 13 apparently sporadic MTC and one of 12 apparently sporadic phaeochromocytomas harboured a similar mutation, but the corresponding germline DNA was wildtype in each case.

Post-transcriptional silencing of RET occurs, but is not required, during raf-1 mediated differentiation of medullary thyroid carcinoma cells

“…Commonly, mutations in extracellular cysteine residues encoded by exons 10 and 11 of RET are associated with two inherited MTC syndromes, familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2A (MEN 2A) (Donis-Keller et al, 1993;Mulligan et al, 1993). The predominant mutation in MEN 2B, a hereditary MTC syndrome more aggressive than MEN 2A, and in sporadic MTC, is a single missense mutation in exon 16 resulting in the replacement of a methionine with a threonine at codon 918 in the tyrosine kinase domain (Carlson et al, 1994;Eng et al, 1994;Hofstra et al, 1994.). These changes in the RET gene have been shown to be activating mutations leading to inappropriate kinase activity (Pasini et al, 1997).…”

Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation

“…About 75% of all MTCs are believed to be sporadic (Bergholm et al, 1990;Raue et al, 1993), and the remaining 25% comprise the autosomal dominant multiple endocrine neoplasia type 2 (MEN 2) syndromes, MEN 2A, MEN 2B and familial MTC (Farndon et al, 1986;Schimke, 1984). Germline mutations of the RET protooncogene a ecting exons 10, 11, 13, 14, 15 and 16 have been found to be associated with MEN 2 (Bolino et al, 1995;Carlson et al, 1994;Donis-Keller et al, 1993;Eng et al, 1994Eng et al, , 1995Farndon et al, 1986;Gimm et al, 1997;Hofstra et al, 1994;Mulligan et al, 1993;Schimke, 1984; Smith et al, 1997). Speci®cally, germline mutation at codon 918 (M918T) in exon 16 is associated with 495% of MEN 2B , which is characterized by a more severe form of MTC and phaeochromocytoma occurring at a young age and classic stigmata such as ganglioneuromatosis and a marfanoid habitus.…”

Multiple endocrine neoplasia 2B with glaucoma associated with codon 918 mutation of the RET proto‐oncogene

“…The same constitutional germline point mutation, ATG (methionine) to ACG (threonine) at codon 918 in the tyrosine kinase domain of the gene was found in 82 (95.3%) of the 86 Caucasian patients with MEN 2B (Eng et al 1994;Carlson et al 1994a;Rossel et al 1995). The same point mutation was also found in three Japanese patients with MEN 2B (Murayama et al 1994).…”

“…This mutation eliminates a FokI site. The primers used for PCR were CRT5G (GA-AAGCAACACCCACACTTACA) and CRT5H (CCTCCTTTACCTCCTTCC-TAGAG) (Eng et al 1994). Direct sequencing confirmed a T-to-C transition at codon 918.…”