A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas

Abstract

The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients’ treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0351-2) contains supplementary material, which is available to authorized users.

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas

“…Furthermore, our observations that IDH-MUT gliomas have reduced numbers of infiltrating T cells may seem contradictory to those of previous studies demonstrating that tumor infiltration by CD8 + T cells is predictive of better patient survival (39)(40)(41). However, it is important to note that human IDH-WT LGGs may be driven by other oncogenic signals that are not present in IDH-MUT tumors, and poor prognosis may indicate that the biology of IDH-WT LGGs more closely resembles that of GBM than of LGGs (42). In our models, genetic backgrounds for IDH-MUT versus IDH-WT cells (with SB28, GL261, and NHA) were the same except for the status of IDH, which is not the case in human…”

Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT

“…Previous studies demonstrated an interaction between the predictive role of MGMT methylation and TERT status in this group [2, 17]. One study showed that the prognostic influence of MGMT promoter methylation depended on the presence of TERT promoter mutations among IDH -mutant glioblastoma patients who were treated with standard chemoradiation [17].…”

“…One study showed that the prognostic influence of MGMT promoter methylation depended on the presence of TERT promoter mutations among IDH -mutant glioblastoma patients who were treated with standard chemoradiation [17]. Another study showed a significant interaction between TERT status and MGMT methylation status among IDH -wildtype glioblastoma patients treated with radiation and temozolamide, and proposed four subgroups [2]. However, they have only provided the hazard ratios without confidence intervals or p values to assess the significance of any of the pairwise associations.…”

cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”

“…The combination of TERT promoter mutation with other markers, such as EGFR amplification and +7/−10 adds specificity as a marker of grade IV behavior [27]. The finding of prognostic interaction of TERT promoter mutations with MGMT promoter methylation in patients with IDH-wildtype glioblastoma treated with radiochemotherapy with temozolomide warrants futher study [3, 21]. …”