Mutations in the Cysteine-Rich Region of the RET Proto-Oncogene in Patients Diagnosed as Having Sporadic Medullary Thyroid Carcinoma

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    • KIMURA Takehiko
    • The First Department of Internal Medicine, School of Medicine, The University of Tokushima
    • YOSHIMOTO Katsuhiko
    • Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima
    • YOKOGOSHI Yutaka
    • The First Department of Internal Medicine, School of Medicine, The University of Tokushima
    • SAITO Shiro
    • The First Department of Internal Medicine, School of Medicine, The University of Tokushima


Medullary thyroid carcinoma (MTC) and pheochromocytoma appear in either a sporadic or a hereditary form as components of multiple endocrine neoplasia (MEN). Many germline mutations of the <i>RET</i> proto-oncogene have been reported in patients with MEN 2A and 2B, and familial MTC(FMTC). To elucidate the etiological roles in tumorigenesis of sporadic MTCs and pheochromocytomas, mutations in the cysteine-rich region of the <i>RET</i> proto-oncogene were analyzed by using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Exons 10 and 11 were studied in genomic DNAs from 3 clinically apparent sporadic MTCs, MTCs and pheochromocytomas from 2 patients with MEN 2A, 1 with FMTC, 4 with MEN 2B, 3 with neurofibromatosis type 1(NF1), 12 sporadic pheochromocytomas and an MTC cell line, TT. All tumors from two patients with MEN 2A and one patient with FMTC had mutations at codon 618 and 634 as well as their leukocytes, reflecting their germline mutations. In this region, no mutations were detected in any tumors from patients with MEN 2B and NF1, and sporadic pheochromocytomas. But mutations were detected and identified in 3 clinically apparent sporadic MTCs and TT cells. A 6 base pair (bp) deletion causing the loss of a cysteine residue at codon 634 and a mutation causing substitution from cysteine to tyrosine at codon 634 were detected in 2 sporadic MTCs as somatic events. In a female patient diagnosed as having sporadic MTC, a mutation at codon 618 was detected not only in tumor tissues, but also in her leukocytes, suggesting a germline mutation of the <i>RET</i> protooncogene. In TT cells a heterozygous mutation at codon 634 was detected. These results suggest that <i>RET</i> mutations within a cysteine-rich region may also play an important role in the tumorigenesis of sporadic MTCs, and mutations of <i>RET</i> protooncogene should be screened in clinically sporadic cases to exclude hereditary MTCs.


  • Endocrine Journal

    Endocrine Journal 42(4), 517-525, 1995-08-01

    The Japan Endocrine Society

References:  31

Cited by:  4


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