Neurosurgery notes/Tumours/Tumour genetics/TERT

TERT

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Tumour genetics

General

  • TERT: Telomerase reverse transcriptase

Gene loci

  • Chromosome 5p15.33.

Normal function

  • Encodes the catalytic telomerase reverse transcriptase subunit that adds telomeric repeats to chromosome ends using the RNA template TERC, maintaining telomere length and genomic stability in stem, germ, and activated immune cells.
  • TERT expression is tightly repressed in most somatic cells and is rate‑limiting for telomerase activity, thereby restricting replicative potential and acting as an anti‑tumor barrier

Mutation effects

  • Recurrent promoter hotspot mutations (C228T, C250T) create de novo ETS transcription factor binding sites, leading to increased TERT transcription and telomerase reactivation, which enables cellular immortalization and supports oncogenic signaling.
    • ETS transcription factor binding sites are short DNA sequences that members of the ETS (E‑twenty six) transcription factor family recognize and bind.
  • Other genetic and epigenetic changes (copy gain, rearrangements, SNPs at the promoter, altered chromatin looping) also upregulate TERT and confer telomere‑independent functions, including modulation of WNT/β‑catenin and other pathways, further promoting tumor progression.
  • TERT promoter mutations can cooperate with oncogenic drivers such as BRAF V600E.

Clinical association

  • TERT promoter gene mutations commonly occur with 1p/19q codeletion
  • TERT promoter gene mutations are mutually exclusive in gliomas TP53 mutations
  • pTERT mutations are commonly found in
      • Oligodendroglioma (78%)
      • LGGs that were positive for all three markers, so called ‘triple positive’, had the best overall survival
        • pTERT mutation with other genetic aberrations, such as IDH mutation and 1p/19q co-deletion
      Grade II and III
      • pTERT mutations alone confer to poorer prognosis
      • pTERT mutations with IDH mutations together confer to better prognosis
      • TERT mutations have poorest prognosis for low grade
          • notion image
          notion image
      Primary glioblastoma multiforme (GBM) (81%)
      • pTERT mutation was present in only 10% of astrocytomas and GBM IDH-mutant (also called secondary GBM)
      • By contrast, in higher-grade gliomas (HGGs) such as GBM the combination of pTERT mutation with IDH mutation and 1p/19q status did not result into a significant discrimination of the overall prognosis
          • Type of mutation
          Overall survival
          TERT promoter mutations
          Median 11.3 months
          Without TERT or IDH1/2 mutations
          Median 16.6 months
          IDH-only mutant GBM
          Median 42.3 months
      Meningiomas
      • Prognostic value of this marker
        • Hotspot C228T and C250T mutations
            • WHO Grade
            Percentage of tumour with mutation
            1
            1.7%
            2
            5.7%
            3
            20.0%
      • Median progression free survival:
        • Mutant: 10.1 months
        • Wildtype: 179 months