Medullary thyroid carcinoma (MTC) occurs sporadically or as part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. In MEN 2A, germline missense mutations are found in one of five cysteine codons within exons 10 and I I in the extracellular domain of the RET protooncogene. In MEN 2B, germline mutations occur in codon 9 I8 (exon 16) within the catalytic core of the tyrosine kinase domain. To determine if RET mutations similar t o those in MEN 2A and 2B play a role in the pathogenesis of sporadic MTC, we analysed 7 I sporadic turnours comprising 68 primary turnours and three cell lines, for mutations in R E J exons 10. I I, and 16. We found that 23% of sporadic MTC had RET codon 9 I8 mutations, while only 3% had exon I0 mutations, and none had mutations in exon I I. We found no exon I 6 mutations in MTC from I 4 MEN 2A cases. Thus, exon I0 and I I mutations, commonly found in familial MTC and MEN 2A, rarely occur in sporadic MTC; somatic mutation of RET codon 9 I8 appears t o play a role in the tumourigenesis of a significant minority of sporadic MTC but not MEN 2A turnours. In addition t o their biological 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. Genes Chromosom Cancer 'I 2r209-2 I2 (I 9c).