A rare subtype of the glial tumor with H3F3B p.K28I in Chinese adult diffuse midline gliomas.
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e14012 Background: Diffuse midline gliomas (DMGs) with H3 K27 altered are extremely aggressive WHO grade IV tumors, with no significant therapeutic progress made in the past. DMGs with H3 K27 altered have been classified as a rare subtype of glial tumor according to 2021 WHO Classification of CNS Tumors. K27M mutation always occurs in the H3F3A gene or HISTIH3B/C gene, and the majority of DMGs harbor H3 K27M-mutation. Studies have been reported that systematic in vitro modification of the lysine 27 predicts K27I as the only substitution other than K27M to result in a repressive effect on H3K27me3. Herein, we reported two adult patients with DMGs harboring somatic H3-K27I mutation. It is important to identify H3 K27-mutation accurately for accurate diagnosis, prognostication, and also for treatment selection. Methods: Next-generation sequencing (NGS) 539-gene panel (Simceredx) profiling was performed using postoperative tissue. The molecular characteristics, K3 K27 mutation types, and other co-mutations were also evaluated. Results: Patient one was a 36-year-old female. Magnetic resonance images (MRI) of the brain were performed and showed the pons tumor in the brainstem. Postoperative pathology showed astrocytoma (WHO Grade II) with diffuse slightly dense cells. NGS results showed that the patient was carried H3F3B exon2 p.K27I (allele frequency, AF 57.64%), TP53 exon7 p.M237I (AF 80.27%). Patient two was a 44-year-old male and was diagnosed with spinal cord glioma, WHO grade III. NGS panel profiling was performed and H3F3B exon2 p.K27I (AF 30.46%), ATRX exon9 p.S1173* (AF 75.23%), KRAS exon2 p.G12A(AF 38.11%) and NF1 intron42 c.6580-1G > A(AF 36.44%) were identified. Conclusions: In our study, we identified the H3F3B K27I mutation in two adult DMG patients by NGS, which expanded the detection gene spectrum of DMG patients. The type of histone H3 mutated could also predict the outcome and accurate diagnosis and glioma grading of DMG patients, which was more efficient than clinical and radiological characteristics of the tumors. Accurate genetic testing should be given more attention to those patients.Keywords:
ATRX
Pons
Angiocentric glioma is a rare, World Health Organization grade I tumor that is seen predominantly in children and young adults and typically presents with seizures. Histologically, it shows features of both infiltrating glioma and ependymoma.We examined molecular immunohistochemical markers which could help in distinguishing this entity from its differential diagnostic considerations.We retrospectively reviewed the clinicopathologic features of angiocentric gliomas and performed immunohistochemical staining for isocitrate dehydrogenase 1 (IDH-1) (R132H), p53, ATRX, BRAF V600E, Ki-67, and H3 K27M on formalin-fixed, paraffin-embedded tissue. Seven cases in total were found and included six excisional specimens and one biopsy. ATRX staining was retained in all cases. There was no evidence of staining with antibodies to IDH-1 (R132H), H3 K27M, or BRAF V600E. Five tumors showed no staining with antibody to p53 and two tumors showed less than 5% positivity. Ki-67 indices were less than 1% in five tumors, 4-5% in one tumor, and 9-10% in one tumor.In conclusion, the immunohistochemical markers for ATRX, p53, IDH-1 (R132H), BRAF V600E, H3 K27M show wild-type staining, potentially aiding in avoiding misdiagnoses in cases morphologically similar to other low-grade gliomas. Ki-67 labeling indices are low in most tumors.
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Isocitrate dehydrogenase
Ependymoma
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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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Oligodendroglial Tumor
Anaplastic astrocytoma
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1. Experimental induction of gliogenous tumors was made by implanting methylcholanthrene pellets into the brain of laboratory animals. Two hundred and forty-two mice of C3H, ddN, CF1, CFW, C57BL strain and 212 rats of Wistar and Donryu strain were employed in this experiment. A total of 112 mice and 21 rats were found to have tumor. By histological examinations, 39 tumors in mice and 13 in rats were classified as gliomas, 8 tumors in mice and 1 in rat as mixed glioma and sarcomas, and the others as mesenchymal tissue tumors. 2. Experimantally produced tumors were successfully transplanted into the brain and the subcutis of animals of the same strain. They were capable of subsequent transfer through a number of generations. The transplants recapitulated the histological features of the parent tissue, but they became less pleomorphic and more undifferentiated in appearance. Experimental gliomas were also successfully transplanted into the heterogeneous strains. 3. By applying the criteria employed in the classification of human glioma, the experimentally produced gliomas were subclassified into glioblastoma, oligodendroglioma-, astrocytoma-, and ependymoma-like tumors. Glioblastomas comprised the majority of total gliomas. This type of glioma was closely mimiced the corresponding histological type of gliomas in man. Gliomas of adult tissue were classified according to the histology in routine sections. By special impregnation techniques and by electron microscopy it became evident that the constituent cells of this type of tumor appeared more or less anaplastic. It is, therefore, not easy to subclassify the experimental gliomas into various distinct histological types as those in man. 4. The frequent production of mixed gliomas, and gliom as mixed with sarcoma was 5. Tumors of mesodermal origin were also produced in die experiments. The frequency of their production constitutes one of the characteristic features of experimental tumors in mice. It is argued mat intracerebral vessels and meninges are possible sources of die experimental tumors of mesodermal origin. 6. Decisive evidences about the problem of topographical peculiarities in different histological types of experimental gliomas were not obtained in this experiment. There was no tumor incidence with the histology of medulloblastoma in man. Therefore, this study failed to afford any evidence that medulloblastoma is a neuroblastoma derived from the adult neurons in the granular layers of the cerebellar cortex.
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Background: The World Health Organization (WHO) 2016 classification incorporated molecular subtyping in glioma, highlighting the diagnostic and prognostic significance. The study aims to determine the isocitrate dehydrogenase (IDH-1) gene, α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, and tumor suppressor gene-53 (p53) mutation in glioma and their correlation with various clinical and radiological parameters.Methods: In this prospective observational study, histopathological slides of glioma (2017-2018), were analyzed for IDH-1, ATRX and p53 mutations and their correlation with various clinical and radiological parameters.Results: IDH-1 mutation was found in 48 (38.7%), ATRX loss in 38 (30.6%) and p53 mutation in 40 (32.5%) patients. The expression of IDH-1 was significantly higher (43.7%) in adults; however, no significant difference was seen with gender. Also 51.2% of patients, who presented with seizures, showed IDH-1 expression; and 27.7% of patients, who had neurological deficit also showed IDH-1 expression. IDH-1 expression was high in glioma located at insula (73.3%) and parietal lobe (71.4%); while ATRX loss was seen in glioma located at insula (80%). Intraventricular glioma characteristically lacks all three markers: IDH-1 expression, p53 overexpression and ATRX loss. IDH-1 expression and p53 overexpression was seen mainly in diffuse fibrillary astrocytoma, oligodendroglioma, anaplastic astrocytoma and glioblastoma.Conclusions: Molecular subtyping is of paramount importance in glioma management. IDH-1 mutation is commonly observed in adults and patients presenting with seizures. The duration of symptoms correlates with IDH-1 and ATRX mutations. Intraventricular tumors lack all three mutations.
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Isocitrate dehydrogenase
Subtyping
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Glioma is the most common of all primary brain tumors with poor prognosis and high mortality. The 2016 World Health Organization classification of the tumors of central nervous system uses molecular parameters in addition to histology to redefine many tumor entities. The new classification scheme divides diffuse gliomas into low-grade glioma (LGG) and glioblastoma (GBM) as per histology. LGGs are further divided into isocitrate dehydrogenase (IDH) wild type or mutant, which is further classified into either oligodendroglioma that harbors 1p/19q codeletion or diffuse astrocytoma that has an intact 1p/19q loci but enriched for ATRX loss and TP53 mutation. GBMs are divided into IDH wild type that corresponds to primary or de novo GBMs and IDH mutant that corresponds to secondary or progressive GBMs. To make the 2016 WHO subtypes of diffuse gliomas more robust, we carried out Prediction Analysis of Microarrays (PAM) to develop DNA methylation signatures for these subtypes. In this study, we applied PAM on a training set of diffuse gliomas derived from The Cancer Genome Atlas (TCGA) and identified DNA methylation signatures to classify LGG IDH wild type from LGG IDH mutant, LGG IDH mutant with 1p/19q codeletion from LGG IDH mutant with intact 1p/19q loci and GBM IDH wild type from GBM IDH mutant with an accuracy of 99–100%. The signatures were validated using the test set of diffuse glioma samples derived from TCGA with an accuracy of 96 to 99%. In addition, we also carried out additional validation of all three signatures using independent LGG and GBM cohorts. Further, the methylation signatures identified a fraction of samples as discordant, which were found to have molecular and clinical features typical of the subtype as identified by methylation signatures. Thus, we identified methylation signatures that classified different subtypes of diffuse glioma accurately and propose that these signatures could complement 2016 WHO classification scheme of diffuse glioma.
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Isocitrate dehydrogenase
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Abstract BACKGROUND The integration of molecular markers into the WHO 2016 classification has clarified the complex diagnosis of gliomas. Among these biomarkers, the TERT promoter mutation and the loss of ATRX (ATRX loss) are mutually exclusive alterations associated with re-activation of telomerase or alternative lengthening of telomeres (ALT), respectively. Strangely, 25% of gliomas display neither or both these alterations, a situation referred to as abnormal telomere maintenance mechanism (aTMM). MATERIAL AND METHODS To investigate the TMM actually involved in gliomas, the C-circle (CC) assay was adapted to tumor (FFPE and frozen) samples. RESULTS We constructed a CC-based algorithm able to identify the TMM of 284 gliomas with either TERT or ATRX alteration, with a sensitivity of 100% and a specificity of 97.3%, and succeeded in deciphering the TMM involved in 122 aTMM gliomas. Additionally, the combination of the TMM, the mutational status of the Isocitrate dehydrogenase 1/2 (IDH) gene, and the histological grading was used as base for a new classification: TeloDIAG. Six subtypes are defined in this classification: tOD, tLGA, tGBM_IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma, respectively, the last class gathers ALT+ IDHwt glioma. The TeloDIAG diagnosis is 99% concordant with the WHO classification for glioma displaying typical molecular characteristics (N=312). It modified the classification of 38% (N=156) discordant tumors, such as IDHwt Astrocytoma, aTMM tumors, or gliomas with unexpected TMM (e.g. TERTwt oligodendroglioma, ATRX loss GBM). Interestingly, 20% (N=69) of TERTwt, ATRXwt, or IDHwt GBM were actually tAIV, which is remarkable as tAIV-glioma patients’ survival tended to be longer (21.2 months) than tGBM patients’ survival (16.5 months). Importantly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 95% (N = 206). CONCLUSION In sum, the TeloDIAG is a new, simple, and efficient tool helping in glioma diagnosis and a promising option for liquid biopsy
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Isocitrate dehydrogenase
Grading (engineering)
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Granular Cell Astrocytoma (GCA) is a rare astrocytic brain tumor histologically composed of plump astrocytic cells with abundant eosinophilic granular cytoplasm that exhibits immunoreactivity for GFAP and S100 proteins. It is associated with poor outcome often akin to glioblastoma despite its bland histologic appearance. We report a case of GCA in which neoplastic cells resembled macrophages on intra-operative frozen section and smear. Paraffin sections showed features of a granular cell astrocytoma, WHO grade IV, with diffuse immunohistochemical coexpression of GFAP and S100. No mutation of IDH1 or P53 was identified by immunohistochemistry; however, ATRX loss indicating mutation supported an astrocytic lineage. Additionally, sporadic weak cytoplasmic staining for CD68 and EMA and negative staining for CD163 is likely non-specific due to increased lysosomal activity and does not indicate true histiocytic or epithelial differentiation. We recommend that in the absence of overt high-grade features or admixture with conventional diffuse astrocytoma on intra-operative smear and frozen section, it may be advisable to wait to confirm the diagnosis on paraffin section histology and immunohistochemical stains before proceeding with definitive tumor resection. This diagnostic approach will prevent over-treatment by resection of non-neoplastic mimics of GCA.
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Following the introduction of the molecular classification of gliomas by the WHO in 2016, molecularly-proven lineage conversion during glioma recurrence has never been reported. The reported two cases were initially diagnosed as oligodendroglioma with 1p/19q-codeletion and mutation of isocitrate dehydrogenase 1 (IDH1)-R132H. The recurrent tumors showed loss of alpha-thalassemia/mental retardation X-linked (ATRX) expression, strong P53 positivity, and 1p/19q-nondeletion. Next generation sequencing analysis performed on the first case confirmed the transition of molecular traits from oligodendroglioma to astrocytoma. An IDH mutation of R132H was preserved in the episodes of recurrence, but ATRX and TP53 mutations were newly acquired and TERT promoter mutation C228T was lost at the most recent recurrence. The issue in question for the presented cases is whether the original tumors were pure oligodendrogliomas that then transdifferentiated into astrocytomas, or whether the original tumor was an oligoastrocytoma having oligodendroglioma cells that outnumbered the astrocytoma cells and where the astrocytoma cells becoming more dominant over the episodes of recurrence. With the recognition of the possibility of lineage conversion, our study suggests that molecular examination should be performed to adjust therapeutic strategies in recurrent gliomas. Indeed, our observation of lineage conversion in glioma recurrence calls into question the current distinction drawn between oligodendroglioma, astrocytoma and oligoastrocytoma, rather than simply bidding "farewell to oligoastrocytoma."
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Oligodendroglial Tumor
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Tumor mutational burden predicts survival in patients with low-grade gliomas expressing mutated IDH1
Gliomas are the most common primary brain tumors. High-Grade Gliomas have a median survival (MS) of 18 months, while Low-Grade Gliomas (LGGs) have an MS of approximately 7.3 years. Seventy-six percent of patients with LGG express mutated isocitrate dehydrogenase (mIDH) enzyme. Survival of these patients ranges from 1 to 15 years, and tumor mutational burden ranges from 0.28 to 3.85 somatic mutations/megabase per tumor. We tested the hypothesis that the tumor mutational burden would predict the survival of patients with tumors bearing mIDH.We analyzed the effect of tumor mutational burden on patients' survival using clinical and genomic data of 1199 glioma patients from The Cancer Genome Atlas and validated our results using the Glioma Longitudinal AnalySiS consortium.High tumor mutational burden negatively correlates with the survival of patients with LGG harboring mIDH (P = .005). This effect was significant for both Oligodendroglioma (LGG-mIDH-O; MS = 2379 vs 4459 days in high vs low, respectively; P = .005) and Astrocytoma (LGG-mIDH-A; MS = 2286 vs 4412 days in high vs low respectively; P = .005). There was no differential representation of frequently mutated genes (eg, TP53, ATRX, CIC, and FUBP) in either group. Gene set enrichment analysis revealed an enrichment in Gene Ontologies related to cell cycle, DNA-damage response in high versus low tumor mutational burden. Finally, we identified 6 gene sets that predict survival for LGG-mIDH-A and LGG-mIDH-O.we demonstrate that tumor mutational burden is a powerful, robust, and clinically relevant prognostic factor of MS in mIDH patients.
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Brain tumor
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