TERT Promoter Mutations Increase Tumor Aggressiveness by Altering TERT mRNA Splicing in Papillary Thyroid Carcinoma

Context Telomerase reverse transcriptase promoter (TERT-p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT-p mutations, but such tumors show less aggressiveness and better prognosis than TERT-p mutation-positive tumors.Objective TERT has multiple splicing variants whose relationships with the TERT-p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT-p mutational status, the TERT splicing pattern, and clinicopathological features.Methods We investigated the expression of 2 major variants, alpha deletion (dA) and beta deletion (dB), in a series of 207 PTCs operated on between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital.Results The TERT-p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into 3 groups: the TERT-p mutation-negative/expression-negative group (mut-/exp-), the TERT-p mutation-negative/expression-positive group (mut-/exp+), and the TERT-p mutation-positive group (mut+/exp+). The +A+B/dB ratio in mut+/exp+ was significantly higher than that in mut-/exp+ PTCs. Analysis with clinicopathological data revealed that +A+B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor-suppressive role.Conclusion These results provide evidence that the TERT-p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness.