title: 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.
authors.affiliation: Department of Pathology, University of Cambridge, UK.
authors.forename: L M
authors.initials: LM
authors.lastname: Mulligan
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: C S
authors.initials: CS
authors.lastname: Healey
authors.forename: D
authors.initials: D
authors.lastname: Clayton
authors.forename: J B
authors.initials: JB
authors.lastname: Kwok
authors.forename: E
authors.initials: E
authors.lastname: Gardner
authors.forename: M A
authors.initials: MA
authors.lastname: Ponder
authors.forename: A
authors.initials: A
authors.lastname: Frilling
authors.forename: C E
authors.initials: CE
authors.lastname: Jackson
authors.forename: H
authors.initials: H
authors.lastname: Lehnert
mesh_terms: D001483:Base Sequence; D018276:Carcinoma, Medullary / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D029721:Drosophila Proteins; D005091:Exons; D006801:Humans; D008969:Molecular Sequence Data; D009377:Multiple Endocrine Neoplasia / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D017931:DNA Primers; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila