New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double <i>RET</i> mutations.

Abstract

The <i>RET</i> proto-oncogene is responsible for the pathogenesis of hereditary (98%) and sporadic (40%) medullary thyroid carcinoma (MTC). In sporadic MTC, somatic <i>RET</i> mutations are associated with a poor prognosis. We looked at the genetic profile of patients with advanced and metastatic MTC. The correlation between these mutations and outcome was also investigated. 70 patients with advanced and metastatic sporadic MTC were studied. Exons 10-11 and 13-16 of <i>RET</i> were analysed by direct sequencing. All cases were studied for <i>RAS</i> and the majority also for <i>TERT</i> mutations. <i>RET/RAS</i>-negative cases were analysed for other oncogene mutations. 64/70 cases (91.4%) showed a somatic mutation, while 6 (8.6%) were negative. Among the mutated cases, <i>RET</i> mutations, mainly M918T, were the most prevalent (93.8%). <i>K-</i> or <i>H-RAS</i> mutations were present in 6.2% of cases and were mutually exclusive with <i>RET.</i> No other mutations were found. Four tumours showed two <i>RET</i> somatic mutations. We found a complex somatic <i>RET</i> alteration in 6/60 (10%) <i>RET</i>-positive sporadic MTC cases. A positive correlation between a poor prognosis and the multiple number of <i>RET</i> mutations was found. This study showed a high prevalence of somatic <i>RET</i> mutations in advanced and metastatic MTCs. <i>RAS</i> mutations were present in a small percentage of cases and mutually exclusive with <i>RET</i> mutations. In a small number of cases, more than one <i>RET</i> mutation was present in the same tissue. <i>RET</i> double mutations and, to a lesser extent, also complex mutations showed a worse outcome.