| Summary: | This study was designed to investigate whether <i>RET</i> (rearranged during transfection) mRNA over-expression could be considered an alternative driver event for the development of medullary thyroid carcinoma (MTC), and if different <i>RET</i> isoforms could play a role in MTC tumorigenesis. Eighty-three MTC patients, whose mutational profile was previously identified by next-generation sequencing (NGS) IONS5, were included in this study. Expression analysis was performed by the quantitative reverse transcription-polymerase chain reaction technique. <i>RET</i> expression levels were found to be significantly higher in cases with <i>RET</i> somatic mutations than in cases that were negative for <i>RET</i> somatic mutations (<i>p</i> = 0.003) as well as in cases with a somatic mutation, either in <i>RET</i> or <i>RAS</i> than in cases negative for both these mutations (<i>p</i> = 0.01). All cases were positive for the <i>RET51</i> isoform expression while only 72/83 (86.7%) were positive for <i>RET9</i> isoform expression. A statistically significant higher expression of the <i>RET51</i> isoform was found in cases positive for <i>RET</i> somatic mutation than in cases either positive for <i>RAS</i> mutation (<i>p</i> = 0.0006) or negative for both mutations (<i>p</i> = 0.001). According to our data, <i>RET</i> gene over-expression does not play a role in MTC tumorigenesis, neither as an entire gene or as an isoform. At variance, the <i>RET</i> gene, and in particular the <i>RET51</i> isoform, is expressed higher in <i>RET</i> mutated cases. On the basis of these results we can hypothesize that the overexpression of <i>RET</i>, and in particular of <i>RET51</i>, could potentiate the transforming activity of mutated <i>RET</i>, making these cases more aggressive.
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