Genotype-Phenotype Correlation of Patients with Multiple Endocrine Neoplasia Type 2 in Japan

Shin Ichi Egawa, Hitoyasu Futami, Kayo Takasaki, Masatoshi Iihara, Takahiro Okamoto, Masako Kanbe, Toshitaka Ohi, Yukie Saio, Akira Miyauchi, Yumi Takiyama, Masafumi Koga, Ken Miyanaga, Ken Ichi Inoue, Shoshu Mitsuyama, Yoshio Nomura, Hiroyuki Takei, Soichi Mugiya, Osamu Ishida, Fujio Zeze, Shiro ShakutsuiHiroyuki Inoue, Hiroyuki Oya, Akira Yoshimura, Shinji Ishizuka, Takeshi Tsujino, Takao Obara, Ken Yamaguchi

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23 Citations (Scopus)


Background: Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and hyperparathyroidism. MEN 2 is caused predominantly by germ-line mutations of the RET proto-oncogene. This study aimed to clarify the genotype-phenotype correlation in MEN 2 patients in Japan in order to modify the clinical management according to the genotype. Methods: Constitutive DNA of 64 MEN 2 patients (48 kindreds) were searched for mutations at exons 10, 11, 13, 14 and 16 of the RET proto-oncogene using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing and restriction enzyme digestion. The clinical characteristics of the patients were obtained from a previous nationwide questionnaire survey. Results: Overall, 62 (96.9%) out of 64 patients had a germ-line point mutation at the hot spots. MTC and pheochromocytoma occurred equally in every genotype except C630S. Specific genotype had a correlation between tumor size and age at the operation for MTC or extent of MTC, i.e. C618S developed late onset type of MTC as compared with that of C634R, C634Y and M918T. Small MTC in C634R may be less aggressive than those in C634Y and M918T. Conclusions: DNA testing has good clinical implications for the management of patients with MEN 2 and the timing and operative procedures of thyroidectomy can be modified according to the genotype.

Original languageEnglish
Pages (from-to)590-596
Number of pages7
JournalJapanese Journal of Clinical Oncology
Issue number10
Publication statusPublished - 1998


  • DNA testing
  • Genotype-phenotype correlation
  • Multiple endocrine neoplasia
  • RET proto-oncogene


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