TERT promoter mutation designates biologically aggressive primary glioblastoma

Large-scale molecular profiling efforts over the past decade have greatly clarified the molecular foundations of the diffuse gliomas, and the robust molecular subclasses of which they are composed.1 Mutations in IDH1/2 and ATRX, for instance, have emerged as prognostically relevant biomarkers that, along with MGMT promoter methylation and 1p/19q codeletion, are now routinely assessed at many institutions. Recently, mutations in the promoter region of the TERT gene, which encodes the enzymatic core of telomerase, were identified in a broad spectrum of cancers, including glioma.2–4 TERT promoter mutations are thought to unmask binding sites for ETS family transcription factors, upregulating TERT expression and cellular telomerase activity.2,3 As cancer cells have a basic need to maintain telomere length during many cycles of mitosis, enhanced telomerase activity would be expected to facilitate cellular immortalization and, in doing so, promote oncogenesis. TERT mutations commonly occur in glioma, and their distribution across glioma variants strikingly correlates with established markers of molecular subclass, including IDH1/2 and ATRX mutations, and 1p/19q codeletion.4 As such, TERT mutations already have considerable potential as prognostic biomarkers across the broad spectrum of diffuse gliomas. Whether TERT mutations designate distinct clinical behavior within primary glioblastomas (GBMs), however, has not been explicitly addressed. In a study published in this issue of Neuro-oncology, Simon et al investigated this very question in a sample set of 192 GBMs.5 Similar to earlier work, they found a high rate of TERT mutations in their cohort (76.6%). Moreover, TERT mutations were much more common in primary versus secondary GBMs, and were inversely correlated with IDH1/2 mutations. This latter finding is consistent with prior studies on lower-grade gliomas (WHO grade II and III), the precursors of secondary GBM. Indeed, the largest subset of lower-grade gliomas harbors virtually no TERT mutations and is instead highly enriched in ATRX mutations and the alternative lengthening of telomeres (ALT) phenotype, a telomerase-independent telomere maintenance mechanism.4,6,7 Simon et al then correlated their genotyping results with outcome data, and found that in the 176 primary GBMs analyzed, TERT-mutant tumors exhibited significantly shorter overall survival than their TERT-wild type counterparts. They also examined how a naturally occurring polymorphism, also in the TERT promoter region, affected disease outcome in GBM patients with and without somatic TERT promoter mutations. Interestingly, GBM patients with the so-called G-allele, which actually eliminates a pre-existing ETS transcription factor binding site within the TERT promoter and downregulates TERT expression, do not exhibit unfavorable prognosis in the context of co-existent TERT promoter mutation. This finding is consistent with earlier work in bladder cancer,8 and suggests that increased TERT expression itself drives aggressiveness in GBM. Moreover, modulating the degree of TERT transcription at the level of its promoter appears to have a significant impact on the inherent malignancy of primary GBM. Finally, Simon et al observed that the unfavorable prognosis conferred by TERT mutation in primary GBM was absent in the setting of gross total resection and temozolomide therapy. These data suggest that the biologically aggressive properties of TERT-mutant GBMs might also render them somewhat more susceptible to cytotoxic therapy. As indicated above, this study is the first to directly address the biological significance of TERT mutation within primary GBMs alone. Its findings demonstrate that TERT mutational status delineates two distinct subgroups of primary GBM that differ in their inherent malignant potential. How TERT mutations segregate with other common molecular abnormalities in GBM, or established primary GBM subclasses (e.g. proneural, mesenchymal, classical, etc.) has not been thoroughly addressed by studies to date.4,9 Such analyses should only enrich our understanding of the distinctions between TERT-mutant and wild type disease. The clinical utility of TERT genotyping in designating prognosis across all diffuse gliomas has already been established. For instance, it has been suggested that TERT mutation coupled with IDH1/2 mutation will eventually supplant 1p/19q codeletion as the de facto molecular signature of oligodendroglioma.4 Similarly, IDH1/2 mutation without TERT mutation (and in the presence of ATRX mutation) designates astrocytic lineage and a somewhat worse prognosis.6,10 Whether the prognostic significance of TERT mutations within primary GBMs will attain a similar degree of clinical significance remains unclear at present, particular given the absence of prognostic stratification between TERT-mutant and wild type tumors in the context of the current standard-of-care (i.e. gross total resection and cytotoxic adjuvant therapy). Should treatment regimens become more diversified as the field progresses toward more targeted paradigms, the biological distinctions between TERT mutant and wild type GBMs may again emerge. In conclusion then, studies like this one continue to demonstrate that TERT mutation represents a key molecular determinant of biological subclass in glioma. At minimum, TERT mutation should be assessed along with other biomarkers of demonstrated prognostic significance moving forward, as clinical trials refine optimal treatment strategies for the different glioma subgroups.