The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas

Abstract

Mutations in the telomerase reverse transcriptase gene promoter (TERTp) are common in glioblastomas (GBMs) and oligodendrogliomas (ODGs), and therefore, have a key role in tumorigenesis and may be of prognostic value. However, the extent of their prognostic importance in various gliomas is controversial. We studied 168 patients separated into five groups: Group 1: 65 patients with ODG carrying an IDH1 or IDH2 mutation (IDH-mutant) and 1p/19q-codeletion, Group 2: 23 patients with anaplastic astrocytoma (AA), IDH-mutant, Group 3: 13 patients with GBM, IDH-mutant, Group 4: 15 patients with AA, IDH-wildtype (WT), and Group 5: 52 patients with GBM, IDH-WT. TERTp mutations were found in 96.9%, 4.4%, 76.9%, 20.0%, and 84.6% of patients in Groups 1, 2, 3, 4, and 5, respectively. The R132H mutation in IDH1 was found in 60.5% (23/38) of patients in the AA cohort (Groups 2 and 4) and 20.0% (13/65) of patients from our GBM cohort (Groups 3 and 5), whereas all patients with ODG (Group 1) had a mutation either in IDH1 (n = 62) or IDH2 (n = 3). Using Kaplan Meier survival analysis, we found that the TERTp mutation was correlated with poor overall survival (OS) in Groups 2 and 4 combined (P = 0.001) and in Group 4 (P = 0.113), and in multivariate analysis, the TERTp mutant group was associated with significantly poor survival in Group 5 (P = 0.045). However, IDH mutation, MGMT methylation, and younger patient age (<55 years old) were significantly correlated with favorable OS (all P < 0.05) in our cohort of astrocytic and ODGs. In patients with ODG (Group 1), mutant IDH and TERTp did not have prognostic value because these mutations were universally present. Based on the revised 2016 WHO classification of gliomas, we found that TERTp mutation was frequently present in patients with GBM or ODG and because it was strongly correlated with poor survival outcome in patients with IDH-WT GBM in multivariate analysis, it may be of prognostic value in this subgroup of patients with gliomas.

Keywords: Alpha-thalassemia/mental retardation syndrome X-linked (ATRX); Anaplastic astrocytoma; Glioblastoma; Isocitrate dehydrogenase (IDH); Oligodendroglioma; Telomerase reverse transcriptase.

Fig. 1

a) MRI showing a solid and cystic mass involving the right frontal lobe with diffuse increased T2 signal intensity in the right frontal lobe, insula, and corpus callosum genu with subfalcine herniation on the left side. b) The tumor is indicative of glioblastoma by the presence of necrosis and microvascular proliferation. c, d) Tumor cells are positive for IDH-1 (H09), R132H-mutant, and retained expression of ATRX

Fig. 2

Recurrent anaplastic astrocytoma, IDH-mutant. a) MRI showing initial tumor and 3 times recurrent tumors despite concurrent chemotherapy and radiotherapy. b) Initial tumor showing a sheet of neoplastic gemistocytic astrocytes with mild to moderate nuclear atypia, WHO grade III. c) The second recurrent tumor shows more pleomorphic nuclei with bizarre tumor cell features than those of initial tumor, but there is neither tumor necrosis nor microvascular proliferation. c, d) However, note IDH-1 and ATRX mutation were sustained (c: IDH1 (H09) staining, d: ATRX immunostaining)

Fig. 3

Electropherograms showing sequence of the TERT promoter region with the two hot-spot mutations a) C250T and b) C228T

Fig. 4

a) All gliomas included in this study showed statistically different survival. b) Among patients with grade III anaplastic astrocytoma (AA), the IDH-mutant group showed remarkably better survival than IDH-WT group. c) The IDH-mutant grade IV GBM group had significantly better survival compared to the IDH-WT GBM group. d) Of all patients with grade III and IV astrocytic tumors, MGMTp-methylated groups have statistically better survival (P = 0.017). e and f) However, when GBM is subdivided into IDH-mutant and IDH-WT, MGMTp-methylation has a modest survival effect (P = 0.051 and P = 0.076, respectively). These results indicate there is no bias effect associated with our group

Fig. 5

a) In group 1 (ODG), we found that TERTp mutations were not associated with OS (P = 0.688). b) In patients with combined group 2 and 4 (total AAs), TERTp- mutant had poorer survival (p = 0.001) than TERTp-WT patients, due to TERTp mutation was more common in poor prognostic IDH-WT AA and older age over 55 years old. c) In patients with grade III IDH-WT AA, the TERTp-mutant group shows poorer OS compared to the TERTp-WT group but was not statistically significant due to shortage of the number of TERTp mutant case (p = 0.113), d) and has no effect on PFS (p = 0.527). e) In the Kaplan-Meier survival analysis, the TERTp-mutation status in patients with grade 4 IDH-WT has no effect on the patient’s OS (P = 0.393). f) A similar finding is seen in the IDH-mutant GBM groups (P = 0.370)

Fig. 6

ATRX mutation was not a statistically significant biomarker in all grade III and IV astrocytic tumors. a) In cases with grade III anaplastic astrocytoma, combined IDH-mutant and –WT tumors, the ATRX-mutant group does not show statistically different OS compared to the ATRX-WT group (P = 0.780), b) a finding which is comparable to that found in the GBM IDH-WT group (P = 0.419). c, d) Statistical significance of age were obtained in the group 4 (AA, IDH-wildtype) (P = 0.029), and the group 5 (IDH-WT GBMs) (P = 0.016), patients older than 55 years have a statistically significant worse OS compared to patients younger than 55 years of age