MUTATIONS IN THE RET PROTOONCOGENE ARE ASSOCIATED WITH MEN 2A AND FMTC

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary t hyroid carcinoma (FMTC) are dominantly inherited conditions which pred ispose to the development of endocrine neoplasia. Evidence is presente d that sequence changes within the coding region of the RET proto-onco gene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single str and conformational variants (SSCVs) in exons 7 and 8 of the RET proto- oncogene were identified in eight MEN 2A and four FMTC families. The v ariants were observed only in the DNA of individuals who were either a ffected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cyste ine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases o f well documented sporadic medullary thyroid carcinoma or pheochromocy toma that were tested for exon 7 variants. Coinheritance of the mutati ons with disease and the physical and genetic proximity of the RET pro to-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, no r the ligand of RET are yet known. However, its apparent involvement i n the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.