Classification based on mutations of TERT promoter and IDH characterizes subtypes in grade II/III gliomas

Abstract

Background: Grade II and III gliomas have variable clinical behaviors, showing the distinct molecular genetic alterations from glioblastoma (GBM), many of which eventually transform into more aggressive tumors. Since the classifications of grade II/III gliomas based on the genetic alterations have been recently emerging, it is now a trend to include molecular data into the standard diagnostic algorithm of glioma.

Methods: Here we sequenced TERT promoter mutational status (TERTp-mut) in the DNA of 377 grade II/III gliomas and analyzed the clinical factors, molecular aberrations, and transcriptome profiles.

Results: We found that TERTp-mut occurred in 145 of 377 grade II and III gliomas (38.5%), mutually exclusive with a TP53 mutation (TP53-mut; P < .001) and coincident with a 1p/19q co-deletion (P = .002). TERTp-mut was an independent predictive factor of a good prognosis in all patients (P = .048). It has been an independent factor associated with a good outcome in the IDH mutation (IDH-mut) subgroup (P = .018), but it has also been associated with a poor outcome in the IDH wild-type (IDH-wt) subgroup (P = .049). Combining TERTp-mut and IDH-mut allowed the grade II/III malignancies to be reclassified into IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt. 1p/19q co-deletion, TP53-muts, Ki-67 expression differences, and p-MET expression differences characterized IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt subtypes, respectively.

Conclusions: Our results showed that TERTp-mut combined with IDH-mut allowed simple classification of grade II/III gliomas for stratifying patients and clarifying diagnostic accuracy by supplementing standard histopathological criteria.

Keywords: IDH mutation; TERT promoter mutation; The Cancer Genome Atlas; grade II/III gliomas; whole transcriptome sequencing.

© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Fig. 1.

Survival of the 4 subgroups stratified according to IDH and TERT promoter mutations. TERTp-mut was a distinct prognostic factor in both the IDH-mut and IDH-wt subgroups. Survival analysis based on IDH and TERT promoter mutational status demonstrated a remarkable stratification (IDH-mut/TERTp-mut versus IDH-mut/TERTp-wt, P < .0001; IDH-mut/TERTp-wt versus IDH-wt/TERTp-wt, P = .0317; IDH-wt/TERTp-mut vs. IDH-wt/TERTp-mut, P = .0495).

Fig. 2.

Key molecular aberrations of grade II/III glioma subgroups. (A) Representative photomicrographs of tumor sections following immunohistochemical analysis for Ki-67, p-MET, and MMP-9 expression (×200). (B) MGMT methylation was enriched in IDH-mut tumors; TP53 mutations mainly occurred in IDH-mut/TERTp-wt tumors, while 1p/19q codeletion dominated in IDH-mut/TERTp-mut; IDH-wt/TERTp-mut tumors and IDH-wt/TERTp-wt tumors expressed high Ki-67 and p-MET, respectively.

Fig. 3.

Graphical summary of key molecular and biological characteristics of grade II/III glioma subgroups. Based on the IDH and TERT promoter mutational status, grade II/III gliomas were stratified into 4 distinct prognosis subgroups. 1p/19q codeletion mainly occurred in the gliomas with both IDH and TERT promoter mutation, which had an oligodendroglial phenotype. Ki-67 protein expression was significantly high in IDH-wt/TERTp-mut tumors (×200). MET, a mesenchymal marker, was phosphorylated in IDH-wt/TERTp-wt tumors (×200). Proneural gene expression phenotype enriched in the IDH-mut subgroup, and these tumors with an oligodendroglioma component were more common in the IDH-mut/TERTp-mut cluster, while in contrast, IDH-mut/TERTp-wt tumors consisted predominantly of pure astrocytoma. Classical gene expression was mostly restricted to the IDH-wt/TERTp-mut cluster, which showed higher Ki-67 expression. The IDH-wt/TERTp-wt cluster was a heterogeneous mixture of the 4 TCGA subtypes, although the mesenchymal expression phenotype was predominant and the phosphorylation level of MET was the highest in IDH-wt/TERTp-wt tumors associated with the worse survival outcome.