Human TERT promoter mutations as a prognostic biomarker in glioma

Abstract

The TERT promoter (pTERT) mutations, C228T and C250T, play a significant role in malignant transformation by telomerase activation, oncogenesis and immortalisation of cells. C228T and C250T are emerging as important biomarkers in many cancers including glioblastoma multiforme (GBM), where the prevalence of these mutations is as high as 80%. Additionally, the rs2853669 single nucleotide polymorphism (SNP) may cooperate with these pTERT mutations in modulating progression and overall survival in GBM. Using liquid biopsies, pTERT mutations, C228T and C250T, and other clinically relevant biomarkers can be easily detected with high precision and sensitivity, facilitating longitudinal analysis throughout therapy and aid in cancer patient management.In this review, we explore the potential for pTERT mutation analysis, via liquid biopsy, for its potential use in personalised cancer therapy. We evaluate the relationship between pTERT mutations and other biomarkers as well as their potential clinical utility in early detection, prognostication, monitoring of cancer progress, with the main focus being on brain cancer.

Occurrence, functionality and abundance of the TERT promoter mutations

“…88,112 The TERT promoter mutations associated with high disease grades and the worst patient survival in gliomas and together with other markers follow histological classification into subgroups with distinct outcomes. 75,[113][114][115][116][117][118][119] An investigation based on editing out of the TERT promoter mutations showed that the local injection of adenine base editor fused to Campylobacter jejuni CRISPR-associated protein 9 inhibited the growth of gliomas harboring those alterations. 120 Those mutations cause aggressiveness in meningioma resulting in reduced patient survival and define a highly aggressive subgroup of patients with pleural mesothelioma.…”

“…132 A polymorphism rs2853669 at the À245 bp position (Figure 1) from the ATG site within the proximal promoter of the TERT gene modulates the effect of the mutations on disease outcome as reported in different cancers. 86,88,106,117,133,134 The variant allele affects an E-box adjacent noncanonical ETS2 site within the proximal region of the TERT promoter. 2,135 Experiments based on bacterial artificial chromosomes identified that as the upstream of the two ETS sites on the TERT promoter.…”

“…In bladder cancer, besides being associated with an increased disease recurrence and poor patient outcome, the specificity of the TERT promoter mutations distinguishes histologically deceptive cancers from benign mimics 88,112 . The TERT promoter mutations associated with high disease grades and the worst patient survival in gliomas and together with other markers follow histological classification into subgroups with distinct outcomes 75,113‐119 . An investigation based on editing out of the TERT promoter mutations showed that the local injection of adenine base editor fused to Campylobacter jejuni CRISPR‐associated protein 9 inhibited the growth of gliomas harboring those alterations 120 .…”

Occurrence, functionality, and abundance of theTERTpromoter mutations

“…A polymorphism rs2853669 at the -245 bp position (Figure 1) from the ATG site within the proximal promoter of the TERT gene modulates the effect of the mutations on disease outcome as reported in different cancers 86,88,106,117,133,134 . The variant allele disrupts a preexisting non-canonical ETS2 site adjacent to an E-box in the proximal region of the TERT promoter 135 .…”

“…In bladder cancer, besides being associated with an increased disease recurrence and poor patient outcome, the specificity of the TERT promoter mutations distinguishes histologically deceptive cancers from benign mimics 88,112 . In gliomas, the TERT promoter mutations associated with high disease grade, worst patient survival, and other markers follow histological classification into subgroups with distinct disease outcomes 75,[113][114][115][116][117][118][119] . An investigation based on editing out of the TERT promoter mutations showed that the local injection of adenine base editor fused to Campylobacter jejuni CRISPR-associated protein 9 inhibited the growth of gliomas harboring those alterations 120 .…”