In summary and as illustrated in Fig. 7, this study demonstrates for the first time that BRAF V600E and TERT promoter mutations cooperatively upregulate TERT expression via the BRAF V600E → MAPK pathway → FOS → GABP → TERT signaling/transcription axis in human cancers. In this process, BRAF V600E/MAP kinase pathway-phosphorylated FOS plays a critical role in oncogenically bridging the BRAF V600E and TERT promoter mutations by acting as a transcriptional factor of the GABPB gene. To a less extent, the BRAF V600E/MAPK pathway also promotes TERT expression via MYC in a TERT promoter mutation-independent manner. The resulting overexpressed TERT has serious oncogenic consequences. This represents a previously unknown molecular mechanism by which the BRAF V600E/MAPK pathway selectively and robustly regulates the mutant TERT, which mechanistically explains the recently observed robust role of the genetic duet of BRAF V600E and TERT promoter mutations in cooperatively promoting the aggressiveness and poor clinical outcomes of several human cancers. This study holds important cancer biological and clinical implications.Fig. 7Oncogenic cooperation of BRAF V600E and TERT promoter mutations. This model illustrates a mechanism for the synergistic oncogenicity between BRAF V600E and TERT promoter mutations in promoting human cancer progression and aggressiveness. This involves promoting TERT expression through the BRAF V600E → MAPK pathway → FOS → GABPB → GABP complex axis for mutant TERT promoter activation; the TERT promoter mutation-independent MYC component promoted by the BRAF V600E/MAPK pathway moderately stimulating TERT expression is also shown