Introduction
Recent advances in molecular genetics over the last decade have facilitated the integration of molecular markers into the diagnosis of brain tumors. The revised 4th edition of the World Health Organization (WHO) classification of Tumours of the Central Nervous System (the CNS WHO 2016) incorporated molecular diagnosis in the diagnostic criteria for the first time in its history [
17]. The
IDH1/2 (
IDH) status plays a crucial role in defining adult diffuse gliomas in the current diagnostic system.
IDH mutation and 1p/19q codeletion are necessary and sufficient to make the diagnosis of oligodendrogliomas regardless of the histology. The 1p/19q codeletion is the key diagnostic marker to delineate oligodendrogliomas and distinguish them from astrocytomas in IDH-mutated tumors. Although the consortium to inform molecular and practical approaches to CNS tumor taxonomy-not official WHO (cIMPACT-NOW) recommended a practical diagnostic scheme for diffuse gliomas based on the results of ATRX/p53 immunohistochemistry [
16], the
ATRX status is only a surrogate and sometimes inconclusive [
24].
TERT promoter mutations are common in oligodendrogliomas and glioblastomas [
4]. We and others have shown that
TERT promoter mutations are frequently observed (> 90%) in oligodendrogliomas with mutant
IDH and 1p/19q codeletion, and that the presence of
TERT promoter mutations is associated with favorable outcomes in IDH-mutated gliomas [
6,
14,
15]. These findings strongly suggest that
TERT promoter mutations may serve as an alternative diagnostic marker for oligodendrogliomas when combined with the
IDH status. Another aspect of
TERT promoter mutation is that this alteration without accompanying
IDH mutation suggests clinically and biologically aggressive characteristics comparable with those of glioblastomas when found in histologically diagnosed as diffuse gliomas [
6]. The presence of the
TERT promoter mutation indicates the underestimation of the tumor grades when observed in grade II–III diffuse gliomas without
IDH mutation. cIMPACT-NOW Update 3 recommended
TERT promoter mutations as one of the three criteria (the other two being either
EGFR amplification or combined whole chromosome 7 gain/chromosome 10 loss) to diagnosis “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV” [
8]. Thus,
TERT promoter mutations serve as a diagnostic marker to delineate histologically verified IDH-wild diffuse astrocytomas with poor outcome comparable with glioblastomas. Evaluation of this marker is becoming an essential part of the routine diagnosis for diffuse astrocytic tumors with wildtype
IDH. The bivalent impact of
TERT promoter mutations on glioma biology depends on the
IDH status, as such, we have previously proposed a molecular classification based on the
IDH and
TERT status, which can efficiently identify diffuse astrocytomas and oligodendrogliomas [
6].
In this study, in order to further understand the diagnostic and prognostic value of TERT promoter mutation, we examined the impact of TERT promoter mutations on survival in a series of IDH-mutated glioma cases using a large retrospective tumor cohort. Our results showed that TERT promoter mutations predict favorable prognosis regardless of 1p/19q status in IDH-mutated gliomas. We propose that TERT promoter mutations are bivalent diagnostic and prognostic markers for adult diffuse gliomas.
Discussion
In this study, we investigated the survival impact of
TERT promoter mutations in a large cohort of 560 IDH-mutated glioma cases with detailed patient data. We confirmed that majority of the
TERT promoter mutations coincided with 1p/19q codeletion in IDH-mutated gliomas. However, there were notable exceptions, that is, 24 IDH-mutated tumors had
TERT promoter mutations but not 1p/19q codeletion, whereas six tumors had 1p/19q codeletion without
TERT promoter mutations. Multivariable analysis incorporating clinical background revealed that the prognostic impact of
TERT promoter mutations was independent from that of 1p/19q codeletion (Table
2). In the subgroup analyses of grade II-III cases, the
TERT-mutated-1p/19q intact group showed a favorable prognosis comparable to that of the
TERT-mutated-1p/19q codeleted group, while the survival curve of the
TERT-wildtype-1p/19q codeleted group was consistent with that of the
TERT-wildtype-1p/19q intact group (Fig.
2a and c). These results of the subgroup analyses support the findings of the multivariable analyses.
A favorable prognostic impact of
TERT promoter mutation in lower grade gliomas with an
IDH mutation has been reported in several studies [
6,
12,
14,
15]. However, whether
TERT promoter mutations have an impact on patient survival independent of 1p/19q codeletion has not been fully investigated. We addressed this point by performing a multivariable analysis, first incorporating clinical factors. Our study also analyzed the prognosis of tumors with the “atypical” genotype of co-mutation in
IDH and
TERT without 1p/19q codeletion. The result of a large-scale retrospective study by Eckel-Passow et al. [
12] indicated that this group of tumors had good prognosis comparable to that of triple-positive tumors, i.e., those with concurrent
IDH mutation,
TERT mutation, and 1p/19q codeletion. On the other hand, a follow-up of this study reported that
TERT promoter mutation was a prognostic factor in 1p/19q codeleted cases, while the impact of
TERT promoter mutation was not significant in 1p/19q intact cases [
19]. However, in these studies,
TERT mRNA expression was used as a surrogate for
TERT mutational status in a considerable number of cases and, therefore, were not conclusive in their evaluation of the value of
TERT promoter mutation as an independent prognostic marker in IDH-mutated gliomas [
12,
19]. Another study involving over 300 IDH-mutated glioma cases also reported that survival of patients with
IDH-
TERT co-mutated tumors and grade II-III histology did not differ according to 1p/19q status [
15]. Our results showed that
TERT promoter mutations in IDH-mutated gliomas predict favorable prognosis regardless of 1p/19q status, highlighting the significant role of
TERT promoter mutations as a prognostic marker. Significantly longer overall survival was seen in the
TERT-mutated, 1p/19q intact, and IDH-mutated cases than in the
TERT-wildtype, 1p/19q intact, and IDH-mutated cases, among patients with a high KPS score (90-100) in our study. Considering that even 1p/19q codeletion was not a prognostic indicator among patients with a low KPS (< 90), it appears that the relevance of molecular prognostic markers depends on the patient’s clinical factors. This needs to be considered in future studies investigating molecular markers.
Although the
TERT-mutated, 1p/19q intact, and IDH-mutated cases showed comparable survival with that of the triple-positive cases, the histology of the former varied. Whether the definition of oligodendroglioma depends on the tumor’s histology or biological behavior anticipated by genotype, which is reflected in patient survival, is a matter for future debate. The current definition of oligodendroglial tumors in the CNS WHO 2016 prefers the latter [
17]. On the other hand, the WHO classification is rapidly shifting from conventional morphology-based diagnosis to molecularly driven disease definition. Recognizing the significant impact of
IDH mutation on the biology of astrocytic gliomas, cIMPACT-NOW update 5 has recently recommended a terminology “astrocytoma, IDH-mutated, grade 4” for the IDH-mutated diffuse astrocytic gliomas with histological/molecular features of glioblastoma, histological diagnosis over-ridden by molecular features [
7]. A diagnosis should reflect the biology of the tumor, the natural course of disease, and/or response to therapy. The present study and other studies have reported that 1p/19q codeletion without accompanying
TERT promoter mutations does not have prognostic benefit [
19]. Of note, all cases with such genotype were histologically diagnosed as oligodendroglial tumors in our series. The combination of
TERT promoter mutations and
IDH mutations is a highly specific biomarker. Considering that very few single genetic alterations can sufficiently define a tumor type (even 1p/19q codeletion needs to be used in combination with
IDH status),
TERT promoter mutation may deserve recognition as a diagnostic marker as well.
The prognostic relevance of WHO grading in IDH-mutated gliomas is controversial, although it is associated with tumor aggressiveness in their wildtype counterparts [
7,
18,
22,
26]. Our results showed that the survival of patients with IDH-mutated 1p/19q codeleted gliomas did not differ between WHO grade II and III cases (Additional file
2: Fig. S4A). The prognostic significance of WHO grading in molecularly proved oligodendrogliomas remains controversial; our result is comparable to another study [
22] but in contrast with others [
19]. As a nature of retrospective study, the differences in treatment variations including chemotherapy and radiation between WHO grading may have an impact on patient outcome. Future studies on oligodendroglial cases with controlled treatment background is warranted to assess this issue [
19]. On the other hand, our results showed that the survival of patients with IDH-mutated astrocytomas differed among grade II, III, and IV tumors (Additional file
2: Fig. S4B); this result is comparable to those of some previous studies [
25] but contrasts with others [
18,
20]. Currently, the diagnosis of WHO grade II and III is essentially based on the mitotic index determined by microscopic observation of diffuse astrocytomas, and this has remained the same in the CNS WHO 2016 classification. Attempts to molecularly define the aggressive type of diffuse astrocytomas have suggested several genetic markers such as
RB1 pathway alterations (e.g.,
CDKN2A/B homozygous deletion or
CDK4 amplification),
PIK3R1 mutation,
PDGFRA amplification, or G-CIMP low type in the methylation cluster [
2,
3,
7,
11,
21,
25]. Of these, the
CDKN2A homozygous deletion has been proposed as a strong prognostic factor in IDH-mutated astrocytomas [
3,
21,
25]. In our series, high histological grade and
CDKN2A homozygous deletion were adverse prognostic factors in IDH-mutated-1p/19q intact gliomas. This is in line with previous reports [
21]. However, the frequency of this copy number change was relatively low and strongly correlated with high histological grades. IDH-mutated glioblastomas without
CDKN2A homozygous deletion still showed poorer prognosis compared with that of lower grade astrocytomas (Additional file
2: Fig. S5C). WHO grade IV was an independent risk factor for survival in the multivariable analysis for all cases (Table
2) and the subsequent subgroup analysis for 1p/19q intact tumors (Additional file
1: Table S3L). Thus, histologically defined grade IV tumors may have a fundamentally different biology from grade II–III tumors [
7]. Further exploration of molecular markers indicating aggressive IDH-mutated astrocytomas is warranted. In the meantime, histologically defined WHO grading still appears to have an impact on the delineation of biologically and clinically malignant astrocytomas with
IDH mutation.
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