Background:
Telomerase reverse transcriptase (TERT) 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 TERT
mRNA expression and its relationship between TERT promoter mutations and clinicopathological features. Methods: We analyzed 159 PTC samples for TERT promoter mutations using direct
DNA sequencing. TERT expression was measured using quantitative reverse transcription polymerase chain reaction. To examine low allelic frequency of TERT promoter mutations with high sensitivity, we used droplet digital polymerase chain reaction (ddPCR). The relationship between the status of the TERT promoter mutation/expression and clinicopathological features including recurrence risk was statistically analyzed. Results:TERT promoter mutations were found in 20 cases (12.6%). However, TERT 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 TERT promoter mutations in three samples (5.4%) using ddPCR. We confirmed a significant association between TERT promoter mutations and aggressive clinicopathological features in this series. The risk of recurrence of TERT mutation-negative/expression-positive
tumors was significantly higher than that of the mutation-negative/expression-negative
tumors, suggesting that TERT 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 TERT 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, TERT expression levels in the mutation-negative PTCs were inversely correlated with patient age and the presence of BRAF mutations. Conclusions: We confirm a strong correlation between the presence of TERT promoter mutations and aggressive clinicopathological features in this PTC series. In addition, there were PTCs showing high TERT
mRNA expression even in the absence of TERT promoter mutations. These cases also showed a significantly higher recurrence rate. Since the TERT promoter mutations are observed only in elderly patients, TERT
mRNA expression can be a useful prognostic marker especially in younger PTC patients.