MUTATIONS IN THE CYSTEINE-RICH REGION OF THE RET PROTOONCOGENE IN PATIENTS DIAGNOSED AS HAVING SPORADIC MEDULLARY-THYROID CARCINOMA

Medullary thyroid carcinoma (MTC) and pheochromocytoma appear in eithe r a sporadic or a hereditary form as components of multiple endocrine neoplasia (MEN). Many germline mutations of the RET proto-oncogene hav e been reported in patients with MEN 2A and 2B, and familial MTC (FMTC ). To elucidate the etiological roles in tumorigenesis of sporadic MTC s and pheochromocytomas, mutations in the cysteine-rich region of the RET proto-oncogene were analyzed by using polymerase chain reaction-si ngle strand conformation polymorphism (PCR-SSCP) analysis. Exons 10 an d 11 were studied in genomic DNAs from 3 clinically apparent sporadic MTCs, MTCs and pheochromocytomas from 2 patients with MEN 2A, 1 with F MTC, 4 with MEN 2B, 3 with neurofibromatosis type 1 (NF1), 12 sporadic pheochromocytomas and an MTC cell line, TT. All tumors from two patie nts with MEN 2A and one patient with FMTC had mutations at codon 618 a nd 634 as well as their leukocytes, reflecting their germline mutation s. In this region, no mutations were detected in any tumors from patie nts with MEN 2B and NF1, and sporadic pheochromocytomas. But mutations were detected and identified in 3 clinically apparent sporadic MTCs a nd TT cells. A 6 base pair (bp) deletion causing the loss of a cystein e residue at codon 634 and a mutation causing substitution from cystei ne to tyrosine at codon 634 were detected in 2 sporadic MTCs as somati c events. In a female patient diagnosed as having sporadic MTC, a muta tion at codon 618 was detected not only in tumor tissues, but also in her leukocytes, suggesting a germline mutation of the RET proto-oncoge ne. In TT cells a heterozygous mutation at codon 634 was detected. The se results suggest that RET mutations within a cysteine-rich region ma y also play an important role in the tumorigenesis of sporadic MTCs, a nd mutations of RET proto-oncogene should be screened in clinically sp oradic cases to exclude hereditary MTCs.