GENOTYPE-PHENOTYPE CORRELATION OF PATIENTS WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE-2 IN JAPAN

Background: Multiple endocrine neoplasia type 2 (MEN 2) is a hereditar y syndrome characterized by medullary thyroid carcinoma (MTC), pheochr omocytoma. and hyperparathyroidism. MEN 2 is caused predominantly by g erm-line mutations of the RET proto-oncogene. This study aimed to clar ify the genotype-phenotype correlation in MEN 2 patients in Japan in o rder to modify the clinical management according to the genotype. Meth ods: 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-oncogen e using polymerase chain reaction-single strand conformation polymorph ism (PCR-SSCP), direct sequencing and restriction enzyme digestion. Th e clinical characteristics of the patients were obtained from a previo us 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. Spec ific genotype had a correlation between tumor size and age at the oper ation for MTC or extent of MTC, i.e. C618S developed late onset type o f MTC as compared with that of C634R, C634Y and M918T. Small MTC in C6 34R may be less aggressive than those in C634Y and M918T. Conclusions: DNA testing has good clinical implications for the management of pati ents with MEN 2 and the timing and operative procedures of thyroidecto my can be modified according to the genotype.