Isocitrate dehydrogenase (IDH) mutations were first identified in diffuse gliomas in 2009 and have since played a crucial role in glioma classification (1, 2). The 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System incorporated IDH classification as a cornerstone diagnostic feature, which has continued in the 2021 update (3, 4). IDH mutations typically result in mutually exclusive amino acid substitutions in genes encoding for the IDH1 (cytoplasmic isoform) or IDH2 (mitochondrial isoform) enzyme (5). Histopathological confirmation, IDH mutation status, and 1p/19q codeletion status allows the molecular stratification of diffuse gliomas into 3 subgroups with significant survival implications: 1) IDH mutant, 1p/19q codeleted oligodendrogliomas; 2) IDH mutant, 1p/19q non-codeleted astrocytoma; 3) IDH wildtype gliomas (3, 6, 7). Though IDH1 and IDH2 mutations are usually mutually exclusive, we report a case seen at our institution of diffuse astrocytoma with progression to secondary glioblastoma and concurrent IDH1/IDH2 mutations.

Our case illustrates the complexity and variability regarding IDH mutations in gliomas. The normal role of IDH1 and IDH2 are to convert isocitrate to alpha-ketoglutarate. Mutations in IDH1/IDH2 result in the conversion of alpha-ketoglutarate to 2-hydroxyglutarate, which functions as an oncometabolite and is a key driver of gliomagenesis (2, 8). Glioma-specific mutations in IDH1 are known to most frequently affect codon 132, while the IDH2 mutations typically affect codon 172 (2, 9). Both mutations are known to be heterozygous and somatic, leading to amino acid substitutions (2, 5, 10). IDH1 and IDH2 enzymatically function in separate subcellular compartments, with IDH1 in cytosol and IDH2 in mitochondria. It has been shown that under hypoxia IDH1 mutated cells have a decreased ability to induce reductive carboxylation and instead rely on oxidative mitochondrial metabolism (11). In contrast, IDH2 mutated cells have shown the ability to maintain reductive carboxylation in a hypoxic state. Therefore, tumor maintenance and oncogenicity may be impacted by hypoxia depending on the mutation status of IDH1 and IDH2, however our understanding of this is limited since the metabolic communication between mutant IDH1 and IDH2 is not yet understood (11). There is a paucity in the literature regarding the different types and frequencies of IDH1/IDH2 mutations in gliomas. A search of the literature identified 4 cases of concurrent IDH1/IDH2 mutations in gliomas similar to our case (12). An additional case of concurrent IDH1 and IDH2 mutations in gliomas was found in the literature (13). This case was a WHO grade 3 astrocytoma and noted to have a prolonged time to recurrence. This case is similar to the 4 cases published by Hartmann et al. in that all are histologically WHO grade 3 (12, 13). In comparison, our case of concurrent IDH1 and IDH2 mutations was histologically WHO grade 4. It could be possible to study survival or outcomes in association with the detection of concurrent IDH1 and IDH2 mutation in gliomas, however we have limited information at this time and thus are unable to theorize further. A query of The Cancer Genome Atlas (TCGA) database of lower grade gliomas and glioblastoma (n=794 samples) identified 2 cases of concurrent IDH1/IDH2 mutations (tendency for mutual exclusivity, p<0.001).

IDH mutated gliomas are known to be a larger percentage of lower grade gliomas while comprise only a small minority of grade 4 gliomas in comparison to IDH wildtype gliomas (14). A more detailed and multi-institutional evaluation of this rare histopathological feature may have an impact on the development of future therapeutic approaches for patients with IDH-mutant gliomas. Although several targeted therapeutic options have been currently investigated for the management of tumors with IDH1 and/or IDH2 mutations, such as acute myeloid leukemias and cholangiocarcinomas, they have still a limited role for the treatment of gliomas (15). The co-presence of IDH1 and IDH2 mutations in patients with glioblastomas, as shown in our case, may suggest the occurrence of currently unknown epigenetic and/or molecular mechanisms whose discovery may likely lead to important advances in patient management and prognosis. As our understanding of concurrent IDH1 and IDH2 mutations in gliomas develops, this directly impacts clinical diagnostic testing standards. In current clinical practice, the immunohistochemical detection of IDH1 R132H in gliomas precludes the obligation to proceed to sequencing and any further information about IDH2 (16). Thus, it is likely that the current rate of concurrent IDH1 and IDH2 mutations in glioma is underestimated. This has further implications in assessing the effectiveness of novel therapeutics in development that target the IDH mutation, with further study necessary to understand the influence of concurrent IDH1 and IDH2 mutations on survival. In our case, both mutations were detected in the same tissue section. The lower VAF of the IDH2 mutation suggests the possibility that the IDH2 mutation is present only in a subset of the cells compared to the IDH1 mutation. At present, it is not possible for us to determine if the mutations were present in the same tumor cells or in distinct tumor cells within the same tissue section. In particular, the investigation of current inhibitors of IDH mutations, epigenetic therapies, and peptide vaccines may significantly benefit from the reports and analyses of these rare cases.

IDH mutations are key diagnostic and prognostic indicators in the management of gliomas. These mutations vary in frequency and type, with little epidemiological data in the literature. Concurrent IDH1/IDH2 mutations are rare and require further study to better evaluate their impact on patients’ prognoses and their response to targeted therapies.

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by University of Texas MD Anderson Cancer Center. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained for the publication of this case report.

All authors contributed to the manuscript writing and preparation of the figures. All authors contributed to the article and approved the submitted version.