<i>TERT</i> mRNA Expression as a Novel Prognostic Marker in Papillary Thyroid Carcinomas

Abstract

<b><i>Background:</i></b> Telomerase reverse transcriptase (<i>TERT</i>) promoter mutations have been found in a subset of papillary thyroid carcinomas (PTCs) and are associated with tumor aggressiveness and worse prognosis. However, little is known about the status of <i>TERT</i> mRNA expression and its relationship between <i>TERT</i> promoter mutations and clinicopathological features. <b><i>Methods:</i></b> We analyzed 159 PTC samples for <i>TERT</i> promoter mutations using direct DNA sequencing. <i>TERT</i> expression was measured using quantitative reverse transcription polymerase chain reaction. To examine low allelic frequency of <i>TERT</i> promoter mutations with high sensitivity, we used droplet digital polymerase chain reaction (ddPCR). The relationship between the status of the <i>TERT</i> promoter mutation/expression and clinicopathological features including recurrence risk was statistically analyzed. <b><i>Results:</i></b><i>TERT</i> promoter mutations were found in 20 cases (12.6%). However, <i>TERT</i> expression was observed not only in the mutation-positive tumors but also in 56 of 139 (40.3%) mutation-negative tumors. Among them, we detected low allelic frequency of <i>TERT</i> promoter mutations in three samples (5.4%) using ddPCR. We confirmed a significant association between <i>TERT</i> promoter mutations and aggressive clinicopathological features in this series. The risk of recurrence of <i>TERT</i> mutation-negative/expression-positive tumors was significantly higher than that of the mutation-negative/expression-negative tumors, suggesting that <i>TERT</i> expression even in absence of a mutation confers a negative influence on PTCs. Moreover, when we reclassified the mutation-negative cases into two groups based on the <i>TERT</i> expression levels: expression-negative/expression levels <80th percentile and expression levels >80th percentile because minimal expression may have a negligible clinical impact, a higher hazard ratio for recurrence was observed. Interestingly, <i>TERT</i> expression levels in the mutation-negative PTCs were inversely correlated with patient age and the presence of <i>BRAF</i> mutations. <b><i>Conclusions:</i></b> We confirm a strong correlation between the presence of <i>TERT</i> promoter mutations and aggressive clinicopathological features in this PTC series. In addition, there were PTCs showing high <i>TERT</i> mRNA expression even in the absence of <i>TERT</i> promoter mutations. These cases also showed a significantly higher recurrence rate. Since the <i>TERT</i> promoter mutations are observed only in elderly patients, <i>TERT</i> mRNA expression can be a useful prognostic marker especially in younger PTC patients.