TUMOR-SPECIFIC MUTATIONS IN THE TYROSINE KINASE DOMAIN OF THE RET PROTOONCOGENE IN PHEOCHROMOCYTOMAS OF SPORADIC TYPE

Sporadic pheochromocytomas, sporadic medullary thyroid carcinomas (MTC s), pheochromocytomas and/or MTCs in multiple endocrine neoplasia (MEN ) 2A or 2B were screened for mutations in the tyrosine kinase domain o f the RET proto-oncogene by direct sequencing of PCR-amplified product s or sequencing subcloned DNAs from PCR-products. All tumors of 4 MEN 2B patients were confirmed to contain a heterozygous missense mutation at codon 918 (ATG-->ACG; Met-->Thr) of the RET proto-oncogene as well as their leukocytes. The same tumor-specific mutations at codon 918 w ere also found in 5/16 (31%) sporadic pheochromocytomas. These results suggest that mutations of the RET proto-oncogene in its tyrosine kina se domain play a role not only as the predisposing gene for MEN 2B, bu t also as a tumorigenic factor for pheochromocytomas of sporadic type.