Clinico-neuropathological Features of Isocitrate Dehydrogenase 2 Gene Mutations in Lower-Grade Gliomas
Diffuse gliomas are the most common and variably aggressive type of primary brain tumor. Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes have been identified in a large proportion of diffuse astrocytomas, oligodendrogliomas, and secondary glioblastomas. Patients with tumors harboring these mutations generally have better outcomes than those with wild-type IDH genes. The status of the IDH gene has been accepted as an important factor for the integrated diagnosis and prognosis of diffuse gliomas in the 2016 World Health Organization (WHO) classification of tumors of the central nervous system. The p.R132H mutation in IDH1 is the most frequently observed among all IDH mutant gliomas. In contrast, mutations in the IDH2 gene, as well as their associated pathological features and other genetic alterations in diffuse gliomas, are detected at a lower frequency and have been relatively less studied.
To determine the pathological and genetic characteristics, as well as the clinical courses of diffuse gliomas harboring IDH2 mutations, a study was conducted on 238 lower-grade gliomas in adult patients. The study used Sanger sequencing to detect mutations in codon 132 of IDH1 and codon 172 of IDH2. Other molecular markers, including p53, alpha-thalassemia X-linked mental retardation (ATRX), telomerase reverse transcriptase (TERT), Lys-27-Met mutations in histone 3 genes (H3K27M), and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, were also evaluated to identify their relationship with IDH2 mutations in gliomas.
Clinical Features of Diffuse Gliomas with IDH2 Mutations
Among the 238 adult patients with lower-grade gliomas, 169 patients (71%) harbored IDH mutations, including 157 patients (66%) with IDH1 mutations and 12 patients (5%) with IDH2 mutations. The characteristics of these 12 IDH2-mutant patients are summarized in Table 1. Seven of these patients were male, and five were female. The patients’ ages at the time of diagnosis ranged from 26 to 75 years, with a median age of 44.5 years and an average age of 42.7 years. Common initial symptoms included seizures and headaches. Eleven of the 12 cases were located in the frontal lobe, while one case was in the parietal lobe.
Pathological and Molecular Features of Diffuse Gliomas with IDH2 Mutations
Among the 12 IDH2 mutant gliomas, the initial histological diagnosis was oligodendroglioma (grade II) in eight patients, anaplastic oligodendroglioma (grade III) in three patients, and anaplastic astrocytoma in one patient. Histologically low-grade tumors (grade II) were more frequent than high-grade ones (grade III) among the IDH2-mutant gliomas.
Ten patients harbored the IDH2 R172K (c.515G>A) mutation, one patient harbored the IDH2 R172W (c.514A>T) mutation, and one patient harbored the IDH2 R172S (c.516G>T) mutation (Figure 1). The IDH2 mutations were frequently associated with TERT promoter mutations (9/12, four patients with C228T mutation and five patients with C250T mutation) and 1p/19q co-deletion (11/12), and were negatively associated with loss of ATRX expression (2/12) and p53 overexpression (2/12). Only one patient, with the onset age of 75 years, showed the features of anaplastic astrocytoma, harbored the IDH2 R172S mutation, and also revealed a loss of ATRX expression and p53 overexpression. This patient was diagnosed with anaplastic astrocytoma, IDH-mutant, WHO grade III. None of the IDH2-mutant gliomas was positive for the H3K27M mutation. Among the ten patients that were available for detecting MGMT promoter methylation, nine patients were found to harbor MGMT promoter methylation (Figure 2).
IDH2 Mutations and Prognosis
IDH mutational status and survival data were available for 214 patients. Kaplan-Meier survival analysis revealed significantly longer progression-free survival (PFS) and overall survival (OS) of patients carrying the IDH mutation than those with IDH wild-type tumors (log-rank test, PFS: P = 0.049; OS: P < 0.001). The median PFS and OS of patients with IDH wild-type gliomas were 45 and 83 months, respectively, whereas the PFS of patients with IDH2-mutant gliomas was 96 months, and only one patient died (18 months after diagnosis). However, there was no significant difference between IDH1 and IDH2 mutant patients (log-rank test, PFS: P = 0.575; OS: P = 0.773) (Figure 3).
Discussion
Mutations in the IDH1 and IDH2 genes have been found frequently in diffuse gliomas. Integrated diagnosis of diffuse glioma requires the assessment of mutations in IDH1/IDH2 and co-deletion of 1p/19q. IDH1 is localized in the cytoplasm, while IDH2 is found in the mitochondrial matrix. The IDH1 R132H mutation is by far the most frequent (noted in >90% of patients) mutation observed in diffuse gliomas among all IDH mutations, and the genetic and epigenetic landscape of IDH1 mutant gliomas has been studied extensively. In contrast to IDH1, IDH2 mutations are relatively rare (3%–5%), and the functional role of IDH2 is less clear. As reported previously, IDH1 is localized in the cytoplasm and peroxisomes, while IDH2 is localized in the mitochondria and participates in the tricarboxylic acid cycle to produce energy. The energy production in IDH2-mutated gliomas may favor oxidative phosphorylation over aerobic glycolysis. However, this hypothesis needs to be verified by focusing on metabolic pathways and general characteristics with more IDH2-mutant gliomas. Biochemical investigations showed that IDH1 and IDH2 mutations differ in D-2-hydroxyglutarate production in gliomas, and thus may impact different cellular pathways and exert different tumorigenic effects. Therefore, in this study, the clinical and pathological characteristics of diffuse gliomas with tumors harboring IDH2 mutations were investigated.
In this study, 12 patients (5%) were found to harbor IDH2 mutations. The IDH2 R172K mutation, accounting for 83.3%, was the most frequent mutation type in IDH2, which was consistent with previous studies. Notably, mutations in IDH1 and IDH2 were mutually exclusive in gliomas. IDH2 mutations were mainly associated with tumors having the morphological features of oligodendroglioma. The data also indicated that IDH2 mutations were mainly found in WHO grade II gliomas, which was different from previous reports. The presence of IDH2 mutations did not correlate with the presence of TP53 mutations and ATRX loss, but a highly significant positive correlation was observed with the presence of 1p/19q co-deletion and TERT promoter mutations. According to the 2016 WHO classification, most cases (11/12) confirmed the integrated diagnosis of oligodendroglioma or anaplastic oligodendroglioma, IDH mutant, and 1p/19q co-deletion. Only one patient, with the onset age of 75 years, showed the features of anaplastic astrocytoma, which was accompanied by ATRX and TP53 mutations. Furthermore, a patient with the IDH2 R172K mutation in combination with 1p/19q co-deletion, as well as a wild-type TERT promoter and loss of ATRX expression, was also found, which was similar to a previously described study. Loss of ATRX expression is a characteristic alteration of astrocytoma, and it is virtually mutually exclusive with 1p/19q co-deletion. These patients may have shown false-positive results for 1p/19q co-deletion and have a complex c-kit and platelet-derived growth factor receptor alpha (PDGFRA) amplification, homozygous cyclin-dependent kinase inhibitor 2A (CDKN2A) and CDKN2B deletions, as well as a loss of heterozygosity on chromosome 17p (including TP53). Therefore, the diagnosis of oligodendroglioma needs further verification.
The study also found that IDH2 mutations are associated with TERT promoter mutations and MGMT promoter methylation. Earlier studies suggested that IDH-mutant gliomas with TERT promoter mutations have a better outcome than corresponding TERT wild-type tumors. Patients with gliomas containing a methylated MGMT promoter benefited from adjuvant therapy. According to the Chinese Glioma Cooperative Group recommendations, the survival patterns can also be refined by sub-grouping by oligodendroglial, astrocytic, or glioblastoma molecular signatures, which could be served as a valuable source of information for comprehensive and precise treatment. Furthermore, studies found that the immunological tumor microenvironment differs in association with IDH mutation status in diffuse gliomas, which may be relevant for immune-modulatory treatment strategies. Patients with oligodendroglial tumors were found to have a better prognosis (median OS of 8 years) compared with patients with astrocytic tumors (median OS of 5 years). Therefore, the data suggest that patients with IDH2 mutations should be sensitive to adjuvant therapy and have a better prognosis. As expected, patients with IDH2-mutant tumors in the cohort had longer PFS and OS than IDH wild-type patients. However, there was no significantly statistical difference. Moreover, there was no significant difference in prognosis between patients with IDH1- and IDH2-mutant tumors in the cohort. This may be due to the small number of IDH2-mutant cases. In addition, it could be the fact that many oligodendroglioma patients with IDH1 mutations also have a good prognosis. Therefore, additional data and further research are needed to accurately describe the prognostic implications of IDH2 mutations.
In conclusion, the results describe the clinical and pathological characteristics of IDH2 mutant gliomas. IDH2 mutations are more frequent in oligodendrogliomas and associate with a better prognosis. IDH2 mutations may segregate in distinct clinico-pathological and genetic subtypes of gliomas, and therefore may merit routine investigation.
doi.org/10.1097/CM9.0000000000000565
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