A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma

Abstract

Multiple endocrine neoplasia type 2 (MEN 2) comprises three clinically distinct, dominantly inherited cancer syndromes. MEN 2A patients develop medullary thyroid carcinoma (MTC) and phaeochromocytoma. MEN 2B patients show in addition ganglioneuromas of the gastrointestinal tract and skeletal abnormalities. In familial MTC, only the thyroid is affected. Germ-line mutations of the RET proto-oncogene have recently been reported in association with MEN 2A and familial MTC. All mutations occurred within codons specifying cysteine residues in the transition point between the RET protein extracellular and transmembrane domains. We now show that MEN 2B is also associated with mutation of the RET proto-oncogene. A mutation in codon 664, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein, was found in all nine unrelated MEN 2B patients studied. The same mutation was found in six out of 18 sporadic tumours.

Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the ron receptor

“…The Kit mutation, which causes human mast cell leukaemia (Furitsu et al, 1993;Tsujimura et al, 1994) and human mastocytosis (Longley et al, 1996), consists of the substitution of a conserved aspartic acid residue located in subdomain VII of the kinase with a neutral residue (Hanks et al, 1988). In the case of the Ret receptor, a genetic alteration ®rst identi®ed in patients with the inherited cancer syndrome Multiple Endocrine Neoplasia type 2B (MEN2B), converts a methionine residue in subdomain VIII of the kinase into threonine (Carlson et al, 1994;Hofstra et al, 1994). Interestingly, the residues mutated in Kit and Ret are highly conserved among the receptor tyrosine kinases, but have di erent identities in the cytosolic, non-receptor tyrosine kinases (Hanks et al, 1988).…”

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

“…RET/PTC1, the one more frequently isolated, is generated by the fusion of RET to the 5'-terminal region of a gene designated H4 (Grieco et al, 1990). In addition, germline RET point mutations, responsible for the inheritance of the MEN2A (multiple endocrine neoplasia type 2A), MEN2B, and FTMC (familial medullary thyroid carcinoma) syndromes (Donis-Keller et al, 1993;Mulligan et al, 1993;Carlson et al, 1994;Hofstra et al, 1994), also lead to an activation of the transforming potential of RET Asai et al, 1995). In most of MEN2A and FMTC cases substitution of extracellular cysteines leads to a constitutive dimerization of the receptor Asai et al, 1995); in contrast, in the majority of MEN2B cases, a M918T mutation causes a change of Ret substrate speci®city Songyang et al, 1995).…”

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).…”