MUTATIONS OF CODON-918 IN THE RET PROTOONCOGENE CORRELATE TO POOR-PROGNOSIS IN SPORADIC MEDULLARY-THYROID CARCINOMAS

The hereditary multiple endocrine neoplasia syndromes types 2A and B ( MEN 2A and B) were recently linked to germline mutations in the RET pr oto-oncogene, altering one of five cysteine residues in exon 10 or 11 (MEN 2A), or substituting a methionine for a threonine at codon 918 in exon 16 (MEN 2B). The latter mutation also occurs somatically in some sporadic medullary thyroid carcinomas (MTC), and has in a previous st udy been correlated with a less favorable clinical outcome. In the pre sent study, 46 MTCs were selected for investigation of the codon 918 m utation. The mutation was found in 29 tumors (63%), and was significan tly correlated with a poor outcome, with regard to distant metastasis or tumor recurrence (p < 10(-4)). Two tumors showed multifocal growth and C-cell hyperplasia, and these patients were therefore also investi gated for germline mutations in exons 10, 11 and 16. The codon 918 mut ation was found only in the tumors, thus of somatic origin. The RET co don 918 mutation may have prognostic impact and therefore preoperative assessment may influence decision-making in the treatment of patients suffering from MTC.