Interaction of BRAF-induced ETS factors with mutant TERT promoter in papillary thyroid cancer

<jats:p>Synergistic effects of <jats:italic>BRAF</jats:italic><jats:italic><jats:sup>V600E</jats:sup></jats:italic> and <jats:italic>TERT</jats:italic> promoter mutations on the poor clinical outcomes in papillary thyroid cancer (PTC) have been demonstrated. The potential mechanism of this phenomenon has been proposed: MAPK pathway activation by the <jats:italic>BRAF</jats:italic><jats:italic><jats:sup>V600E</jats:sup></jats:italic> mutation may upregulate E-twenty six (ETS) transcription factors, increasing <jats:italic>TERT</jats:italic> expression by binding to the ETS-binding site generated by the <jats:italic>TERT</jats:italic> promoter mutation; however, it has not yet been fully proven. This article provides transcriptomic insights into the interaction between <jats:italic>BRAF</jats:italic><jats:italic><jats:sup>V600E</jats:sup></jats:italic> and <jats:italic>TERT</jats:italic> promoter mutations mediated by ETS factors in PTC. RNA sequencing data on 266 PTCs from The Cancer Genome Atlas and 65 PTCs from our institute were analyzed for gene expression changes and related molecular pathways, and the results of transcriptomic analyses were validated by <jats:italic>in vitro</jats:italic> experiments. <jats:italic>TERT</jats:italic> mRNA expression was increased by the coexistence of <jats:italic>BRAF</jats:italic><jats:italic><jats:sup>V600E</jats:sup></jats:italic> and <jats:italic>TERT</jats:italic> promoter mutations (fold change, 16.17; <jats:italic>q-</jats:italic>value = 7.35 × 10<jats:sup>−12</jats:sup> vs no mutation). In the ETS family of transcription factors, <jats:italic>ETV1</jats:italic>, <jats:italic>ETV4</jats:italic> and<jats:italic> ETV5</jats:italic> were upregulated by the <jats:italic>BRAF</jats:italic><jats:italic><jats:sup>V600E</jats:sup></jats:italic>/MAPK pathway activation. These <jats:italic>BRAF</jats:italic><jats:italic><jats:sup>V600E</jats:sup></jats:italic>-induced ETS factors selectively bound to the mutant <jats:italic>TERT</jats:italic> promoter. The molecular pathways activated by <jats:italic>BRAF</jats:italic><jats:italic><jats:sup>V600E</jats:sup></jats:italic> were further augmented by adding the <jats:italic>TERT</jats:italic> promoter mutation, and the pathways related to immune responses or adhesion molecules were upregulated by <jats:italic>TERT</jats:italic> expression. The mechanism of the synergistic effect between <jats:italic>BRAF</jats:italic><jats:italic><jats:sup>V600E</jats:sup></jats:italic> and <jats:italic>TERT</jats:italic> promoter mutations on cancer invasiveness and progression in PTC may be explained by increased <jats:italic>TERT</jats:italic> expression, which may result from the <jats:italic>BRAF</jats:italic>-induced upregulation of several ETS transcription factors.</jats:p>