TERT, the target?

See the article by Spiegl-Kreinecker et al., pp. 1584–1593

Since 2013, when 2 hotspot point mutations were identified in the telomerase reverse transcriptase (TERT) promoter in melanomas, this genetic event was found to be among the most common point mutations in several tumor entities.^1–5 Thus, TERT is in the research focus of many scientists in different branches of oncology. For neuro-oncology, it is of pivotal interest due to its high frequencies in several brain tumors, most notably glioblastoma and oligodendroglioma.^4,6

Although at lower frequency, TERT mutations are also found in meningiomas. Several studies have provided evidence that TERT promoter mutations are associated with rapid recurrence and malignant progression in meningioma. First studies revealed the association with higher-grade meningioma and recurrence, subsequently the correlation with progression-free survival was reported, and more recent reports identified an enrichment of TERT mutations in secondary meningiomas.^4,7–11 This correlation is already mentioned in the update of the World Health Organization (WHO) classification, and TERT status may emerge as the first molecular prognostic marker for meningiomas.¹² Still, a further understanding of the mechanisms involved in its tumor promoting effects is needed. This insight could hold great potential to ultimately result in novel treatment approaches. The most intuitive assumption is to assign this effect to the activation of telomerase, fostering stabilization of the genome and allowing for immortalization of the neoplastic cell. Indeed, the role of TERT activation for telomere maintenance has been extensively investigated.

In the current issue of this journal, Sabine Spiegl-Kreinecker and colleagues investigated a series of 128 meningiomas for TERT promoter mutations, 121 of which were subjected to propagation in vitro and further assessment of telomerase activity and telomere length.¹³TERT mutational status was associated with increased TERT mRNA expression and telomerase activity. However, in the in vitro analysis, TERT mutations but not their potential effectors—telomerase activity or expression—were significantly associated with cell immortalization. This may point toward, firstly, that mechanisms other than promoter mutation can result in similar levels of telomerase activity, including TERT promoter methylation status or rearrangement of TERT. Secondly, the findings of Spiegl-Kreinecker and colleagues also indicate that, when present, TERT promoter mutation is the decisive factor driving robust cell propagation.

Subsequently, they tested for the effects of inhibiting the increased E-twenty-six (ETS) transcription factor binding resulting from the promoter mutation. Indeed, the ETS inhibitor YK-4-279 increased chemosensitivity. While their aforementioned findings on lack of correlation between telomerase activity and TERT mRNA expression could imply a non-canonical role of TERT, the effect of YK-4-279 was accompanied by downregulation of TERT mRNA expression. Thus, the axis of TERT promoter mutation, the increase in ETS-dependent activation, and the TERT mRNA expression is functional in their model and can be inhibited. This may have implications for the treatment of high-grade meningiomas but also other TERT mutant entities. Yet, it does not fully resolve the discrepancy of correlations between TERT promoter mutation, telomerase activity, and TERT expression with immortalization in vivo.

Particularly for meningioma, a therapy approach based on TERT aberration must consider its heterogeneity and evolution in this entity. So far, it is not known whether all meningiomas could potentially acquire a TERT mutation and subsequently transform into an aggressive high-grade case, or if certain meningiomas are particularly prone to this alteration. DNA methylation studies imply that aggressive meningiomas have a distinct epigenetic pattern, detectable already before other molecular or histological indications of aggressiveness become apparent.^14–16 These high-grade epigenetic groups are, in turn, those that harbor TERT mutations. Hence, TERT mutations may arise on the background of a meningioma already set to develop aggressively. Further studies are warranted to validate this concept and to detect potential differences in the cell of origin of low-grade and high-grade meningioma.

If treatments employing TERT as target get within reach for clinical application, these open questions on TERT evolution and alternative mechanisms of telomerase activation become of pivotal importance toward this therapeutic goal for treatment-refractory meningiomas.