MUTATION OF THE RET PROTOONCOGENE IN SPORADIC MEDULLARY-THYROID CARCINOMA

Medullary thyroid carcinoma (MTC) occurs sporadically or as part of th e inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. in MEN 2A, germline missense mutations are found in one of five cyste ine codons within exons 10 and 11 in the extracellular domain of the R ET protooncogene. In MEN 2B, germline mutations occur in codon 918 (ex on 16) within the catalytic core of the tyrosine kinase domain. To det ermine if RET mutations similar to those in MEN 2A and 28 play a role in the pathogenesis of sporadic MTC, we analysed 71 sporadic tumours c omprising 68 primary rumours and three cell lines, for mutations in RE T exons 10, 11, and 16. We found that 23% of sporadic MTC had RET codo n 918 mutations, while only 3% had exon 10 mutations, and none had mut ations in exon 11. We found no exon 16 mutations in MTC from 14 MEN 2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN 2A, rarely occur in sporadic MTC; somatic mutation of RET cod on 918 appears to play a role in the tumourigenesis of a significant m inority of sporadic MTC but not MEN 2A tumours. In addition to their b iological interest, these findings may have some clinical application in determining whether a patient presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome.