IDH1 and IDH2 mutations in different histologic subtypes and WHO grading gliomas in a sample from Northern Brazil
Igor Andrade PessôaFernanda do Espírito Santo SagicaNilson Praia AnselmoJosé Reginaldo Nascimento BritoEdivaldo Herculano Corrêa de Oliveira
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Glioma is a term used to describe tumors derived from glial cells.These tumors are divided into subgroups based on the histological morphology and similarity of their differentiated glia cells.Traditionally, they are classified according to the World Health Organization and include astrocytomas, oligodendrogliomas, ependymomas, and oligoastrocytomas.Like most cancers, gliomas develop as a result of genetic changes that accumulate with tumor progression.Alterations in isocitrate dehydrogenase 1 (IDH1) and IDH2 were found to be relevant in the classification and prognostic of gliomas.Because of the importance of mutations in these genes, particularly in ©FUNPEC-RP www.funpecrp.com.brGenetics and Molecular Research 14 (2): 6533-6542 (2015)IDH1, in different proposals of the genesis and progression of gliomas, we analyzed the occurrence of mutations in these genes in samples obtained from patients from Belém (PA, Brazil) using polymerase chain reaction-single-strand conformation polymorphism followed by sequencing.We compared the results obtained from tumors of different malignancy grades, evaluating the significance of the associations between different variables.R132H was the only mutation found in 17.6% (6/34) of cases, including in astrocytomas, anaplastic astrocytomas, oligodendroglioma, and anaplastic oligoastrocytoma.No mutations were found in the IDH2 gene.We found no significant relationship between the identified mutations in IDH1 and the variables.Our data could not confirm that mutations in IDH1/IDH2 are indicative of malignancy and prognosis.However, the results support that the mutation in IDH1 gene was an early event in the development of gliomas, as it was found in tumors of different malignancy grades.Keywords:
IDH2
Isocitrate dehydrogenase
Anaplastic astrocytoma
Grading (engineering)
Oligodendroglial Tumor
Abstract PURPOSE We are developing a 48-gene OncoPanel (Kagoshima Brain Tumor 48 OncoPanel) specializing in glioma diagnosis. Clinical application of genetic diagnosis derived from genetic alterations detected by OncoPanel, including IDH mutation, 1p/19q-codeletion, and other gene mutations in lower-grade glioma was verified. METHODS The 48 genes consist of 24 genes related to glioma and 24 genes on chromosomes 1 and 19. DNA was extracted from tumor FFPE samples and blood samples, and then single nucleotide variants and copy number variants were detected using next-generation sequencer. RESULTS Among the 99 diffuse glioma cases that had undergone OncoPanel analysis by July 2019, 40 cases diagnosed histologically as WHO grade 2 or 3 diffuse glioma were included. The integrated diagnosis by conventional gene analysis were Diffuse astrocytoma 10 cases, anaplastic astrocytoma 11 cases, oligodendroglioma 10 cases, anaplastic oligodendroglioma 9 cases. IDH1 mutation was detected in 30 cases, of which in 19 cases 1p/19q-codeletion was detected, all with TERT mutation. Among 11 cases with 1p/19q-non-codeletion, ATRX mutation was detected in 10 cases and was almost mutually exclusive with TERT mutation. In 10 cases without IDH mutation, EGFR amplification or mutation was detected in 6 cases, of which 4 cases were accompanied by TERT mutation. DISCUSSION KBT48 can detect TERT and ATRX mutations in a mutually exclusive manner and can improve the classification accuracy of oligodendroglioma and astrocytoma. Groups with gene profiles similar to glioblastoma with EGFR amplification/mutation and TERT mutation can also be classified. CONCLUSIONS In the diagnostic classification of lower-grade glioma, KBT48 can well classify into oligodendroglioma group, astrocytoma group and glioblastoma-like group, and is considered to be applicable in clinical practice.
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To investigate mutation status of isocitrate dehydrogenase (IDH) 1 and IDH2 genes in Chinese patients with gliomas in correlation with clinicopathological characteristics.Formalin-fixed and paraffin-embedded (FFPE) tissue samples of 234 gliomas were collected including the matched blood samples in 30 patients. DNA was extracted, followed by PCR-Sanger sequencing to detect IDH1 and IDH2 gene mutations. Immunohistochemistry was performed using mutation-specific antibody recognizing IDH1R132H mutation. Immunostains for p53 and epidermal growth factor receptor (EGFR) were also performed. Oligodendroglial tumors with IDH mutation were double stained with IDH1R132H and GFAP by immunofluorescence to investigate the location of IDH1R132H expression.(1) By IDH1 heterozygous somatic mutation analysis, Arg132His (c: G395A) was found in 31.6% (74 of 234) of the cases. IDH mutations were more frequent in oligoastrocytomas (9/13), anaplastic oligoastrocytomas (7/11), oligodendrogliomas(18/26, 69.2%), anaplastic oligodendrogliomas (8/10), and less frequent in diffuse astrocytomas (17/47, 36.2%), anaplastic astrocytomas (5/18), and glioblastomas (10/69, 14.5%). The mutation rate inversely correlated with the tumor grade in a linear fashion in astrocytic tumors (P = 0.007). Primary glioblastomas were characterized by a lower frequency of mutations than secondary glioblastomas (5/55 vs. 5/14, P = 0.036); IDH mutation was not detected in pilocytic astrocytoma and ependymoma. No IDH2 mutation was identified in this study cohort. (2) Immunohistochemistry of IDH1R132H demonstrated a strong cytoplasmic staining in 80 cases, which was highly correlated with IDH mutation status (P = 0.001). IDH1R132H was highly specific to tumor cells. (3) p53 immunostain was significantly correlated the IDH mutation in diffuse astrocytoma, anaplastic astrocytoma and secondary glioblastomas (P = 0.007, 0.026, 0.038 respectively). (4) No correlation between EGFR and IDH mutation was found.High prevalence of IDH heterozygous somatic mutation occurs in the earlier stage of gliomas, which can be detected by mutation-specific antibody IDH1R132H. Furthermore, evaluation of p53 and EGFR expression combined with IDH mutation analysis may significantly aid in the diagnosis and differential diagnoses of gliomas in Chinese patients.
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Anaplastic astrocytoma
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Gliomas account for 45% of all intracranial tumors. Newer technologies have allowed deeper genetic and epigenetic analysis leading to the discovery of IDH (Isocitrate dehydrogenase) mutations and their association with ATRX (alpha-thalassemia/mental retardation syndrome X-linked) and p53, for better diagnosis and prognosis. In this study, we analysed their expression and correlated with various clinicopathological parameters. A follow up to prognosticate gliomas based on the molecular findings is also attempted.During last 5 years both retrospective and prospective cases were included in the study. Immunohistochemistry for IDH1, ATRX, and p53 was done and reported based on intensity and percentage of tumor cells expressing the markers.A total of 53 cases of gliomas were included, excluding primary glioblastomas and ependymomas. The patient's age ranged from 10 to 53 years. The male to female ratio was 1.3:1. IDH1 positivity was seen in 88% of diffuse astrocytoma, 80% of anaplastic astrocytoma, 90% of oligodendroglioma, 60% of anaplastic oligodendroglioma, and 54% of glioblastoma. A significant association was seen between positive IDH1 expression and low-grade gliomas (p = 0.028). A combined analysis of expression of IDH1 and ATRX versus IDH1, ATRX, and p53 with WHO grade showed a statistically significant association. A follow-up of 32 patients was available. Out of 24 IDH1+ (positive) cases, 22 patients had a median survival of 21.5 months (92%). Out of 8 IDH1- (negative) cases, 5 had a median survival of 15.8 months (62%).Gliomas expressing IDH1 mutation show improved survival of patients. Combined analysis of IDH1, ATRX, and p53 has diagnostic and prognostic significance. For routine cases of gliomas, a combination of IDH1 and ATRX are sufficient; however, the use of p53 is recommended for further prognostication and for possible targeted therapy in the future.
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Isocitrate dehydrogenase
Anaplastic astrocytoma
Oligodendroglial Tumor
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IDH2
Isocitrate dehydrogenase
Anaplastic astrocytoma
Oligodendroglial Tumor
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Objective To investigate the expression and significance of isocitrate dehydrogenase 1( IDH1) genic mutation in different subtypes of human gliomas. Methods DNA sequencing and immunohistochemistry were used to detect Levels of IDH1mutation and gene expression in 125 samples of glioma( observation group),11 samples of other central nervous system( CNS) neoplasms( group A) and 10 samples of brain tissue in decompression operation( group B) were detected by direct DNA sequencing and immunohistochemistry. Results IDH1 mutation was detected in diffuse astrocytoma,oligodendroglioma,oligoastrocytoma,anaplastic astrocytoma,anaplastic oligodendroglioma,anaplastic oligoastrocytoma and glioblastoma in observation group. IDH1 mutation was not detected in pilocytic astrocytoma,ependymoma,anaplastic ependymoma,medulloblastoma,group A and B. The differences in IDH1 mutation rate between primary with secondary glioblastomas,and diffuse astrocytoma with pilocytic astrocytoma were statistically significant( P = 0. 02,P = 0. 007). Conclusion IDH1 mutation is a somatic mutation,which is found only in some glioma subtypes,so it can be used as a molecular marker for glioma subtypes.
Isocitrate dehydrogenase
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Ependymoma
Oligodendroglial Tumor
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Isocitrate dehydrogenase
Anaplastic astrocytoma
Pilocytic astrocytoma
Oligodendroglial Tumor
Ependymoma
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Mutations in isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 are found frequently in malignant gliomas and are likely involved in early gliomagenesis. To understand the prevalence of these mutations and their relationship to other genetic alterations and impact on prognosis for Japanese glioma patients, we analyzed 250 glioma cases. Mutations of IDH1 and IDH2 were found in 73 (29%) and 2 (1%) cases, respectively. All detected mutations were heterozygous, and most mutations were an Arg132His (G395A) substitution. IDH mutations were frequent in oligodendroglial tumors (37/52, 71%) and diffuse astrocytomas (17/29, 59%), and were less frequent in anaplastic astrocytomas (8/29, 28%) and glioblastomas (13/125, 10%). The pilocytic astrocytomas and gangliogliomas did not have either mutation. Notably, 28 of 30 oligodendroglial tumors harboring the 1p/19q co‐deletion also had an IDH mutation, and these alterations were significantly correlated ( P < 0.001). The association between TP53 and IDH mutation was significant in diffuse astrocytomas ( P = 0.0018). MGMT promoter methylation was significantly associated with IDH mutation in grade 2 ( P < 0.001) and grade 3 ( P = 0.02) gliomas. IDH mutation and 1p/19q co‐deletion were independent favorable prognostic factors for patients with grade 3 gliomas. For patients with grade 3 gliomas and without 1p/19q co‐deletion, IDH mutation was strongly associated with increased progression‐free survival ( P < 0.0001) and overall survival ( P < 0.0001), but no such marked correlation was observed with grade 2 gliomas or glioblastomas. Therefore, IDH mutation would be most useful when assessing prognosis of patients with grade 3 glioma with intact 1p/19q; anaplastic astrocytomas account for most of these grade 3 gliomas. ( Cancer Sci 2012; 103: 587–592)
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The molecular characteristics of glioma patients, such as 1p/19q codeletion, MGMT promoter region methylation, and IDH1/IDH2 mutations, carry important information for tumor classification, biological behavior, and the prediction of patient survival. We sought to address the clinical characteristics of brain tumor patients in the Taiwanese population. Our aim was to compare the H&E-based classification and the 2016 WHO classification in glioma patients. 192 patients were recruited in this study including glioblastomas (GBMs) and lower-grade gliomas (LGGs). We performed assays to determine the statuses of 1p/19q codeletion, MGMT promoter methylation, and IDH mutations in tumors and assessed their associations with survival time. We also compared the difference between H&E and WHO 2016 classification. Using the H&E classification, the overall survival time (OST) was associated with IDH status in astrocytoma and oligoastrocytoma patients but not in oligodendroglioma and GBM patients. However, OST showed no significant correlation with MGMT promoter methylation in all the groups. Furthermore, no significant association was observed between 1p/19q codeletion and OST in GBM patients. Using the WHO 2016 classification, our results indicated that astrocytoma and oligodendroglioma patients with mutant IDH showed a significantly prolonged OST than patients with wild-type IDH. However, only oligodendroglioma patients with MGMT hypermethylation demonstrated statistically significant difference. Prognostic factors, including the age at diagnosis, IDH mutations, MGMT promoter methylation, and 1p/19q codeletion, could independently predict patient survival. Based on the WHO 2016 classification of glioma, the new histological groups provide a better and objective method to categorize glioma patients and predict patient survival.
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The discovery of the oncometabolite 2-hydroxyglutarate in isocitrate dehydrogenase 1–mutated (IDH1-mutated) tumor entities affirmed the role of metabolism in cancer. However, large databases with tissue metabolites that are modulated by IDH1 mutation remain an area of development. Here, we present an unprecedented and valuable resource for tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and tumor treatments in 101 tissue samples from 73 diffuse glioma patients (24 astrocytoma, 17 oligodendroglioma, 32 glioblastoma), investigated by NMR-based metabolomics and supported by RNA-Seq. We discovered comparison-specific metabolites and pathways modulated by IDH1 (IDH1 mutation status cohort) and tumor entity. The Longitudinal investigation cohort provides metabolic profiles of untreated and corresponding treated glioma samples at first progression. Most interestingly, univariate and multivariate cox regressions and Kaplan-Meier analyses revealed that tissue metabolites correlate with progression-free and overall survival. Thus, this study introduces potentially novel candidate prognostic and surrogate metabolite biomarkers for future prospective clinical studies, aiming at further refining patient stratification in diffuse glioma. Furthermore, our data will facilitate the generation of so-far–unanticipated hypotheses for experimental studies to advance our molecular understanding of glioma biology.
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Glioma is a term used to describe tumors derived from glial cells.These tumors are divided into subgroups based on the histological morphology and similarity of their differentiated glia cells.Traditionally, they are classified according to the World Health Organization and include astrocytomas, oligodendrogliomas, ependymomas, and oligoastrocytomas.Like most cancers, gliomas develop as a result of genetic changes that accumulate with tumor progression.Alterations in isocitrate dehydrogenase 1 (IDH1) and IDH2 were found to be relevant in the classification and prognostic of gliomas.Because of the importance of mutations in these genes, particularly in ©FUNPEC-RP www.funpecrp.com.brGenetics and Molecular Research 14 (2): 6533-6542 (2015)IDH1, in different proposals of the genesis and progression of gliomas, we analyzed the occurrence of mutations in these genes in samples obtained from patients from Belém (PA, Brazil) using polymerase chain reaction-single-strand conformation polymorphism followed by sequencing.We compared the results obtained from tumors of different malignancy grades, evaluating the significance of the associations between different variables.R132H was the only mutation found in 17.6% (6/34) of cases, including in astrocytomas, anaplastic astrocytomas, oligodendroglioma, and anaplastic oligoastrocytoma.No mutations were found in the IDH2 gene.We found no significant relationship between the identified mutations in IDH1 and the variables.Our data could not confirm that mutations in IDH1/IDH2 are indicative of malignancy and prognosis.However, the results support that the mutation in IDH1 gene was an early event in the development of gliomas, as it was found in tumors of different malignancy grades.
IDH2
Isocitrate dehydrogenase
Anaplastic astrocytoma
Grading (engineering)
Oligodendroglial Tumor
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