Mutation of RET proto-oncogene in Families of multiple endocrine neoplasia type 2

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Multiple endocrine neoplasia types 2A and 2B (MEN 2A and 2B) and familial or sporadic medullary thyroid carcinomas (MTC) are associated with mutations in the RET proto-oncogene located at chromosome 10q11.2. We investigated the spectrum of RET mutations among Japanese patlents with these diseased (representatives of 39 families with MEN2 or FMTC,and 33 sporadic MTCs). Mutations in nucleotide sequences encoding one of three specific cyteine residues in the extracellular domain of RET protein were found in 31 of the 32 MEN2A patients and all three FMTC patients examined. A mutation at codon 918, causing the substitution of threonine for methionine in the tyrosine kinase domain of the protein, was found in germline DNAs of all four patients with MEN2B and in 7 of the 33 sporadic MTCs. Germline mutations of codon 768, GAG to GAC (Glu to Asp), were detected in two patients with sporadic MTCs. We also identified two novel somatic mutations in sporadic MTCs, one at codon 631 (Asp to Gly) and the other at codon 634 (Cys to Arg). These two mutations will contrlbute to study functional domains of the RET protein.