Table 1.
Studies of Mechanisms Underlying the Synergistic Interactions between BRAFV600E and TERT Promoter Mutations in Cancer
| Study | Study subjects (n) | Suggested mechanism |
|---|---|---|
| Melanoma | ||
| Vallarelli et al. (2016) [78] | Cell lines of melanoma (8) and melanocytes (1) | TERT promoter mutations form a direct link between TERT expression and MAPK pathway activation due to BRAF or NRAS mutations via the transcription factor ETS1 in melanoma. |
| Li et al. (2016) [79] | Cell lines of melanoma (7) | RAS-ERK signaling activation by BRAFV600E or NRAS mutations maintains an active chromatin state at the mutant TERT promoters in melanoma, facilitating the recruitment of RNA polymerase II and thereby leading transcriptional activation of TERT. |
|
| ||
| Glioma | ||
| Gabler et al. (2019) [80] | Cell lines of glioma (12) | BRAFV600E-induced expression and phosphorylation of ETS1 enhance TERT expression and TERT promoter activity in gliomas with both mutations of BRAFV600E and TERT promoter. |
|
| ||
| Thyroid cancer | ||
| Liu et al. (2018) [69] | Cell lines of thyroid cancer (8), melanoma (7), colon cancer (1), embryonic kidney (1), thyrocytes (1) | BRAFV600E/MAPK pathway promotes phosphorylation and binding of the FOS transcription factor to the GABP promoter, increasing GABPB expression and formation of the GABPA-GABPB complex. This complex selectively binds and activates the mutant TERT promoter, upregulating TERT expression in human cancer. |
| Song et al. (2019) [68] | Tissue samples of papillary thyroid cancer (331; 266 from TCGA and 65 from their own cohort); cell lines of thyroid cancer (8; 2 papillary and 6 anaplastic thyroid cancers) and thyrocytes (2) | ETS transcription factors, such as ETV1, ETV4, and ETV5, which are upregulated by BRAFV600E/ MAPK pathway activation, selectively bind to the mutant TERT promoter in thyroid cancer. TERT expression is increased by the coexistence of BRAFV600E and TERT promoter mutations, and the pathways related to immune response or adhesion molecules are activated by TERT expression. |
| Bullock et al. (2019) [81] | Tissue samples of normal thyroid (59) and papillary thyroid cancer (498; all from the TCGA cohort); cell lines of thyroid cancer (3; 1 papillary and 2 anaplastic thyroid cancers) and thyrocytes (1) | ETV5 is the most transcriptionally upregulated ETS gene in papillary thyroid cancer and is strongly correlated with BRAF and RAS mutational status. ETV5 preferentially binds the mutant TERT promoter allele and enhances TERT transcription, cooperating with FOXE1 to further increase TERT promoter activity. |
TERT, telomerase reverse transcriptase; MAPK, mitogen-activated protein kinase; ETS, E-twenty six; RAS-ERK, RAS-extracellular signal-regulated kinase; FOS, fos proto-oncogene; GABP, GA-binding protein; TCGA, The Cancer Genome Atlas; ETV, ETS variant transcription factor; FOXE1, forkhead box E1.