Prognostic Impact of TERT Promoter Mutations in Adult-Type Diffuse Gliomas Based on WHO2021 Criteria

Abstract

Mutation in the telomerase reverse transcriptase promoter (TERTp )is commonly observed in various malignancies, such as central nervous system (CNS) tumors, malignant melanoma, bladder cancer, and thyroid carcinoma. These mutations are recognized as significant poor prognostic factors for these tumors. In this investigation, a total of 528 cases of adult-type diffuse gliomas diagnosed at a single institution were reclassified according to the 2021 WHO classifications of CNS tumors, 5th edition (WHO2021). The study analyzed clinicopathological and genetic features, including TERTp mutations in each tumor. The impact of known prognostic factors on patient outcomes was analyzed through Kaplan-Meier survival and Cox regression analysis. TERTp mutations were predominantly identified in 94.1% of oligodendrogliomas (ODG), followed by 66.3% in glioblastoma, IDH-wildtype (GBM-IDHwt), and 9.2% of astrocytomas, IDH-mutant (A-IDHm). When considering A-IDHm and GBM as astrocytic tumors (Group 1) and ODGs (Group 2), TERTp mutations emerged as a significant adverse prognostic factor (p = 0.013) in Group 1. However, within each GBM-IDHwt and A-IDHm, the presence of TERTp mutations did not significantly impact patient prognosis (p = 0.215 and 0.268, respectively). Due to the high frequency of TERTp mutations in Group 2 (ODG) and their consistent prolonged survival, a statistical analysis to evaluate their impact on overall survival was deemed impractical. When considering MGMTp status, the combined TERTp-mutated and MGMTp-unmethylated group exhibited the worst prognosis in OS (p = 0.018) and PFS (p = 0.034) of GBM. This study confirmed that the classification of tumors according to the WHO2021 criteria effectively reflected prognosis. Both uni- and multivariate analyses in GBM, age, MGMTp methylation, and CDKN2A/B homozygous deletion were statistically significant prognostic factors while in univariate analysis in A-IDHm, grade 4, the Ki-67 index and MYCN amplifications were statistically significant prognostic factors. This study suggests that it is important to classify and manage tumors based on their genetic characteristics in adult-type diffuse gliomas.

Keywords: IDH-mutant astrocytoma; MGMT promoter; TERT promoter; genetics; glioblastoma; oligodendroglioma.

Figure 1

The Kaplan–Meier survival analysis was conducted on adult-type diffuse gliomas. In this cohort, all gliomas exhibited significant differences in OS (a) and PFS (b). Within the A-IDHm group, there were statistically different OS (c) based on CNS WHO grade, but PFS (d) did not show a significant difference. In the ODG group, histologic grade only impacted patients’ PFS (e,f).

Figure 2

Within group 1, patients with astrocytic tumors, encompassing A-IDHm and GBM-IDHwt TERTp mutations had a significant impact on OS (a) and PFS (b). There was no statistically significant difference in survival between TERTp hotspot C228T and C250T mutations (c,d). There were no significant prognostic differences between classic and molecular GBM (e,f).

Figure 3

In group 2 (ODGs), both OS (a) and PFS (b) were not affected by the TERTp mutation. TERTp mutation did not affect the PFS of grade 2 ODG (c) but had a significant effect on PFS in grade 3 ODG (d). Additionally, the hotspot mutation type did not exhibit a significant association with OS (e) and PFS (f).

Figure 4

In GBM-IDHwt patients, TERTp mutation was not associated with OS (a) and PFS (b). When GBM-IDHwt patients were divided into four groups on TERTp mutation and MGMTp methylation status, the Kaplan–Meier survival analysis revealed statistically significant differences in OS (c) and PFS (d).

Figure 5

TERTp mutations did not have a prognostic impact on OS (a,c) and PFS (b,d) in A-IDHm, grade 4 patients and grade 3 patients.