TERT Promoter Mutation Assay

Telomerase reverse transcriptase (TERT) is the rate-limiting catalytic subunit of telomerase, which maintains telomere length. The two most commonly impacted sites for TERT promoter mutations are located 124 and 146 base pairs upstream from the translational start site, and generate C to T transitions (-124C>T and -146C>T). These two hotspots comprise 100% of the mutations reported in glioma, and >98% of the mutations detected in the TERT promoter across all tumor types. TERT promoter mutations create novel binding sites for ETS/TCF family of transcription factors such as GA Binding Protein Transcription Factor Subunit Alpha (GABPA) and increase TERT expression ~2-6 fold. The -146C>T mutation also creates a binding site for non-canonical NF-KB subunit p52 and ETS1/2.

Somatic mutations in the TERT promoter have been shown to cause TERT upregulation in a wide range of solid cancers, including central nervous system tumors, melanoma, urothelial carcinoma, poorly differentiated and anaplastic thyroid carcinomas, cutaneous basal cell and squamous cell carcinomas, and hepatocellular carcinoma. In glioma and glioblastoma multiforme (GBM), the frequency of TERT promoter mutations varies by WHO grade. Assessment of TERT promoter mutation status, in addition to IDH mutations and 1p/19q co-deletion, could help refine the WHO 2016 classification of gliomas in diagnosis and allow for precise clinical management of the patients.