Mutational Spectrum of Multiple Endocrine Neoplasia Type 2 and Sporadic Medullary Thyroid Carcinoma in Taiwan

Background/Purpose: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant cancer predisposition syndrome, and >95% of MEN 2 patients carry rearranged during transfection (RET) protooncogene mutants. We aimed to elucidate the genotype and phenotype relationship of RET proto-oncogene mutations in Taiwanese subjects with medullary thyroid cancer (MTC). Methods: We genotyped the MEN-2-associated germ-line mutations by PCR-based sequencing of the RET gene. DNA was extracted from a total of 69 members from eight unrelated families with individuals affected by MTC, and from seven sporadic cases of MTC. Results: RET mutations were found in four MEN 2A families, all at codon 634 (one with C > R, two with C > r, and one with C > W). One MEN 2A patient carried a de novo mutation at codon 634 (C > R). In two families of MEN 213, all carried the mutation at codon 918 (M > T). These two cases of MEN 2B were all de novo mutations. One family of familial MTC or unclassified MEN 2 carried the codon 620 (C > F) mutation. Among the seven sporadic cases of MTC, none was found to carry any mutation in hotspot exons. Only two non-synonymous variants (T278N/exon 4 and D489N/exon 7) were found in two cases. However, these two variants were not uncommon in our elderly population. Conclusion: We found that all eight MTC patients with a family history or with the other phenotypes of MEN 2 had RET mutations, whereas no significant RET mutation was found in seven patients with isolated MTC without family history and other endocrine diseases. Molecular scanning of the RET gene in MEN 2 and MTC in Taiwanese patients probably should be limited to exons 10, 11 and 16, initially to be costeffective. [J Formos Med Assoc 2009;108(5):402-408]