BRAF-induced EHF Expression Affects TERT in Aggressive Papillary Thyroid Cancer.

CONTEXT

BRAFV600E and TERT promoter mutations in papillary thyroid carcinoma (PTC) have a synergistic effect on prognosis. This effect is believed to arise from MAPK activation triggered by BRAFV600E, leading to the upregulation of ETS transcription factors that bind to the mutant TERT promoter.

OBJECTIVES

To explore the role of ETS factors in relation to clinical features, BRAFV600E, and TERT promoter mutations in PTC.

DESIGN

Transcriptomic data for 28 ETS factors were analyzed in the PTC cohort of The Cancer Genome Atlas (n = 399) and subsequently validated in a local cohort (n = 93). In vitro experiments were performed to investigate the regulatory role in relation to BRAFV600E and TERT expression.

RESULTS

The Cancer Genome Atlas identified ETS1, ERG, FLI1, GABPA, EHF, ETV6, and SPDEF as differentially expressed genes between stages I + II and III + IV. In both cohorts, EHF was consistently associated with adverse clinical features, BRAFV600E and TERT promoter mutation/expression. Notably, in BRAFV600E mutated PTC, high EHF expression was associated with shorter disease-free survival. Cases harboring concurrent BRAFV600E, TERT promoter mutations, and high EHF expression exhibited the shortest disease-free survival. In cells harboring concurrent BRAFV600E and TERT promoter mutation, overexpression of EHF significantly increased TERT expression, whereas knockdown or pharmacological inhibition of BRAF significantly decreased both EHF and TERT expression. In addition, chromatin immunoprecipitation and quantitative PCR analysis suggested a potential binding of EHF in TERT promoter mutant cells but not in TERT promoter wild-type cells.

CONCLUSION

The ETS transcription factor EHF is associated with poor prognosis in PTC. This is potentially mediated by BRAF-induced upregulation of EHF, which in turn increases TERT expression in TERT promoter mutated cells.