A SINGLE MISSENSE MUTATION IN CODON-918 OF THE RET PROTOONCOGENE IN SPORADIC MEDULLARY-THYROID CARCINOMAS

The RET proto-oncogene is expressed in human medullary thyroid carcino ma and pheochromocytoma. Recently germline mutations of the RET proto- oncogene were reported in four syndromes (MEN 2A, MEN 2B, familial med ullary thyroid carcinoma and Hirschprung's disease) and somatic mutati on was also found in sporadic medullary thyroid carcinoma. To determin e the incidence of RET mutations in medullary thyroid carcinoma in Jap an, we investigated 14 medullary thyroid carcinomas (comprising I case of MEN 2A, 1 case of MEN 2B, 2 cases of familial medullary thyroid ca rcinoma and 10 cases of sporadic). Tumors from all cases were screened by PCR-SSCP on exons 10 and 11. DNA sequencing on these exons was per formed for the hereditary medullary thyroid carcinoma cases. The PCR p roducts of exon 16 from tumor DNA were analyzed by means of Fok1 restr iction enzyme digestion analysis and mutations confirmed by DNA sequen cing. We found no structural abnormalities in either exon 10 or exon 1 1 in any of the cases examined, but in four of 10 sporadic cases we de tected a common point mutation at codon 918 (ATG to ACG) in exon 16, w here methionine was replaced with threonine. Our results support the t heory that a point mutation of exon 16 of the RET proto-oncogene may b e related to the oncogenesis of sporadic medullary thyroid carcinomas. However, further studies on the entire RET proto-oncogene are needed to clarify the relationship between its expression and thyroid tumorig enesis.