Germ Line Mutations of the ret Proto‐oncogene in Japanese Patients with Multiple Endocrine Neoplasia Type 2A and Type 2B

We investigated mutations of the ret proto‐oncogene in Japanese patients with multiple endocrine neoplasia (MEN) type 2A and type 2B. DNAs from pheochromocytomas and/or medullary thyroid carcinomas (MTCs) of five MEN 2A and three MEN 2B patients were amplified by a polymerase chain reaction (PCR) and analyzed. Tumors of four MEN 2A patients had missense mutations in Cys 634 in the extracellular domain of the ret proto‐oncogene. The same mutations were detected in normal tissues of the patients, indicating that the mutations had arisen in the germ line. Using a reverse transcriptase(RT)‐PCR, both normal and mutant transcripts of the ret proto‐oncogene were detected in a tumor of one patient with MEN 2A mutation. In addition, three MEN 2B patients examined had the same point mutation (ATGÂG) at codon 918 in the tyrosine kinase domain of the ret proto‐oncogene. Since all mutations identified in this study generated new restriction enzyme sites or eliminated a restriction site, the mutant alleles of affected family members could be readily detected without sequencing.