The unique oncogene duet of coexisting BRAF V600E and TERT promoter mutations is an important recent discovery in human cancer as a robust genetic background for the development of the most aggressive disease in several cancers. For example, it is strongly associated with the most aggressive clinicopathological outcomes of PTC, with hazard ratios for disease recurrence and patient mortality ranging from 30 to 50 compared with patients harboring neither mutation24,27; PTC-specific mortality nearly exclusively occurred in patients harboring the oncogene duet of BRAF V600E and TERT promoter mutations24,25. Similar robust synergistic role of this oncogene duet in poor clinicopathological outcomes was seen in other human cancers22,23. This genetic duet occurs in about 7–8% PTC5,24,27 and 20–25% melanoma9,22, which correspond to the percentages of the cancer cases with the most aggressive diseases and poorest clinical outcomes. These results suggest that this oncogene duet is a superiorly selected genetic event from an evolutionary perspective. As such, it represents a robust genetic mechanism that underpins aggressive oncogenesis and progression of human cancers and hence ominous clinical outcomes39. A fundamental question remains unanswered, however, as to how this oncogene duet cooperates mechanistically, particularly with respect to how BRAF V600E is functionally linked to the mutant TERT, in cooperatively driving human cancer aggressiveness.