MUTATIONAL ANALYSIS OF THE RET PROTOONCOGENE IN 71 JAPANESE PATIENTS WITH MEDULLARY-THYROID CARCINOMA

Multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and fam ilial medullary thyroid carcinomas (FMTC) are caused by germline mutat ions in the RET proto-oncogene. To investigate the spectrum of RET mut ations among Japanese patients, we screened the RET gene in 71 patient s with thyroid carcinomas. The panel included representatives of 44 fa milies carrying FMTC or MEN2, 22 sporadic medullary thyroid carcinomas (MTCs), and five MTCs without familial information. Mutations in nucl eotide sequences encoding one of three specific cysteine residues in t he extracellular domain of the RET protein were found in 33 of the 34 MEN2A patients and in five of the six FMTC patients examined. A mutati on at codon 918, causing the substitution of threonine far methionine in the tyrosine kinase domain of the protein, was found in germline DN As of all four patients with MEN2B and in two of the 22 patients with sporadic MTCs; codon 918 was mutated somatically in tumor DNAs from th ree other sporadic cases. Germline mutations of codon 768, GAG to GAC (Glu to Asp), were detected in one FMTC, in one patient with sporadic MTC, and in one of the patients without familial information. Two soma tic mutations, an Asp to Gly substitution at codon 631 and a Cys to Ar g substitution at codon 634, had not been reported previously. Of five germline mutations found among the 22 sporadic cases, four were confi rmed as de novo mutations since in each case neither parent carried th e mutation. As nearly one-fourth of the patients with sporadic MTCs ca rried germline mutations and 50% of their children are expected to dev elop MTC and other endocrine tumors, these results indicated the impor tance of careful clinical surveillance of family members of any patien t with MTC.