Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma

Abstract

Medullary thyroid carcinoma (MTC) occurs sporadically or as part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. In MEN 2A, germline missense mutations are found in one of five cysteine codons within exons 10 and 11 in the extracellular domain of the RET protooncogene. In MEN 2B, germline mutations occur in codon 918 (exon 16) within the catalytic core of the tyrosine kinase domain. To determine if RET mutations similar to those in MEN 2A and 2B play a role in the pathogenesis of sporadic MTC, we analysed 71 sporadic tumours comprising 68 primary tumours and three cell lines, for mutations in RET exons 10, 11, and 16. We found that 23% of sporadic MTC had RET codon 918 mutations, while only 3% had exon 10 mutations, and none had mutations in exon 11. We found no exon 16 mutations in MTC from 14 MEN 2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN 2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumourigenesis of a significant minority of sporadic MTC but not MEN 2A tumours. In addition to their biological interest, these findings may have some clinical application in determining whether a patient presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome.

The Glu632-Leu633 deletion in cysteine rich domain of Ret induces constitutive dimerization and alters the processing of the receptor protein

“…These mutations speci®cally occur at codons 609, 611, 618, 620 and 634 and universally result in the substitution of a cysteine residue (Mulligan et al, 1993;Donis-Keller et al, 1993). A single point mutation at codon 918, causing the substitution of a methionine (ATG) with a threonine (ACG), is associated with both MEN 2B and sporadic MTC (Eng et al, , 1995bCarlson et al, 1994;Hofstra et al, 1994;Muragaki et al, 1995;Blaugrund et al, 1994). Approximately 80% of sporadic MTCs are positive for this speci®c RET codon 918 mutation (Eng et al, 1995b(Eng et al, , 1996.…”

“…A single point mutation at codon 918, causing the substitution of a methionine (ATG) with a threonine (ACG), is associated with both MEN 2B and sporadic MTC (Eng et al, , 1995bCarlson et al, 1994;Hofstra et al, 1994;Muragaki et al, 1995;Blaugrund et al, 1994). Approximately 80% of sporadic MTCs are positive for this speci®c RET codon 918 mutation (Eng et al, 1995b(Eng et al, , 1996. In contrast, two other relatively rare somatic mutations, at codons 768 (exon 13) and 883 (exon 15), are detected in approximately 10% of sporadic MTCs (Bolino et al, 1995;Eng et al, 1995a;Komminoth et al, 1995).…”

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.…”

Genomic structure and chromosomal localization of the human GDNFR-α gene

“…Germline mutations of the RET proto-oncogene are found in the majority of cases of multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant syndrome classically characterized by medullary thyroid carcinoma (MTC), phaeochromocytoma (phaeo) and hyperparathyroidism (Mulligan et al, 1993Donis-Keller et al, 1993;Carlson et al, 1994;Eng et al, , 1995Hofstra et al, 1994;Bolino et al, 1995). Somatic activating RET mutations have also been found in sporadic MTC and phaeochromocytoma (reviewed in Eng and Mulligan, 1997).…”