BRAF V600E is another major human oncogene that was also initially discovered in melanoma and subsequently widely found in other human cancers11, including thyroid cancer, particularly papillary thyroid cancer (PTC)12. This mutation causes constitutive activation of the BRAF kinase and consequent oncogenic activation of the mitogen-activated protein kinase (MAPK) pathway through phosphorylating MEK and ERK. It has been widely observed that BRAF V600E is associated with aggressiveness of human cancer, as exemplified by increased tumor recurrence and disease-specific mortality of PTC13,14 as well as clinicopathological aggressiveness of melanoma15,16 and other cancers such as colorectal cancer and brain tumor15,17,18. TERT promoter mutations were similarly associated with increased aggressiveness of human cancers, as exemplified by increased tumor recurrence and disease-specific mortality of PTC5 and aggressiveness of melanoma9,19, glioma, and bladder cancer20,21. Interestingly, BRAF V600E was widely found to be associated with TERT promoter mutations in human cancers, particularly thyroid cancer and melanoma2,5,6,9,19,22,23. When separated from each other, either mutation alone had only a modest effect while coexisting BRAF V600E and TERT promoter mutations were associated with robustly increased cancer aggressiveness, as exemplified by increased lymph node metastasis, distant metastasis, advanced tumor stage, tumor recurrence, and disease-specific mortality of PTC24–27. In a recent large meta analysis on PTC5, the prevalence of coexistence of BRAF V600E and TERT promoter mutations was 7.7% (145/1892), which impressively numerically corresponds to the conventionally known <10% of patients with PTC that has the poorest clinical outcomes. In melanoma, coexistence of BRAF V600E and TERT promoter mutations was associated with increased tumor thickness, high mitotic rate, lymph node metastasis, presence of ulceration, absence of regression, high risk of tumor recurrence, and melanoma-specific mortality22,23.