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Brain Tumor Pathology Apr 2018In this study, we reclassified 400 consecutive glioma cases including pediatric cases, using the revised 2016 WHO classification with samples collected from the Kyushu...
In this study, we reclassified 400 consecutive glioma cases including pediatric cases, using the revised 2016 WHO classification with samples collected from the Kyushu University Brain Tumor Bank. The IDH1/2, H3F3A, key genetic markers in the 2016 classification, were analyzed using high-resolution melting, with DNA extracted from frozen tissues. The 1p/19q codeletions were evaluated using a microsatellite-based loss of heterozygosity analysis, with 18 markers, to detect loss of the entire chromosome arm. In the integrated diagnosis, 29 oligodendroglioma cases and 28 anaplastic oligodendroglioma cases were diagnosed as "IDH-mutant and 1p/19q-codeleted," while 2 oligodendroglioma cases and 5 anaplastic oligodendroglioma cases were diagnosed as not otherwise specified (NOS). These "NOS" cases were either IDH-mutants or 1p/19q-codeleted, although characteristic oligodendroglial features were evident histologically. Better overall survival of patients with oligodendroglioma correlated with the molecular characteristic of "IDH-mutant and 1p/19q-codeleted," rather than the WHO grade. Eleven "glioblastoma, IDH-wild-type" cases were classified as "1p/19q-codeleted", however, chromosome 10 loss was also detected in 10 out of 11 cases. The 2016 WHO criteria for glioma classification leads to better diagnosis of patients. However, there are technical pitfalls and problems to be solved in the molecular analysis of routine diagnostics.
Topics: Brain Neoplasms; Chromosomes, Human, Pair 10; DNA; Databases, Factual; Gene Deletion; Genetic Markers; Glioma; Histones; Humans; Isocitrate Dehydrogenase; Loss of Heterozygosity; Microsatellite Repeats; Mutation; Pathology, Molecular; Survival; World Health Organization
PubMed: 29569163
DOI: 10.1007/s10014-018-0313-4 -
AJNR. American Journal of Neuroradiology Apr 2018The 2016 revision of the mandates codeletion of chromosomes 1p and 19q for the diagnosis of oligodendroglioma. We studied whether conventional MR imaging features could...
BACKGROUND AND PURPOSE
The 2016 revision of the mandates codeletion of chromosomes 1p and 19q for the diagnosis of oligodendroglioma. We studied whether conventional MR imaging features could predict 1p/19q status.
MATERIALS AND METHODS
Patients with previous 1p/19q testing were identified through pathology department records, typically performed on the basis of an oligodendroglial component on routine histology; 69 patients met the inclusion criteria. Preoperative imaging of patients with grade II or III gliomas was retrospectively assessed by 2 neuroradiologists, blinded to the 1p/19q status. Thirteen MR imaging features were first assessed in a small initial cohort ( = 10), after which the criteria were narrowed for the remaining patients as a validation cohort.
RESULTS
There was 85% agreement between radiologists for the overall prediction of 1p/19q status in the validation cohort, with an accuracy of 84%. The presence of >50% T2-FLAIR mismatch and calcification was found to be the most useful for predicting 1p/19q status. The >50% T2-FLAIR mismatch variable was demonstrated in 14 tumors and had 100% specificity for identifying a noncodeleted tumor ( = .001), with 97% interobserver correlation. Calcification was visualized in 7 tumors, 6 of which were 1p/19q codeleted (specificity, 97%; = .006), with 100% interobserver correlation.
CONCLUSIONS
The presence of >50% T2-FLAIR mismatch is highly predictive of a noncodeleted tumor, while calcifications suggest a 1p/19q codeleted tumor. If formal 1p/19q testing is not possible, a combined MR imaging-histologic assessment may improve the diagnostic accuracy over histology alone.
Topics: Adult; Brain Neoplasms; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Cohort Studies; Female; Glioma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Retrospective Studies
PubMed: 29519793
DOI: 10.3174/ajnr.A5572 -
The Neuroradiology Journal Aug 2018Purpose We explored whether advanced magnetic resonance (MR) imaging techniques could grade oligodendrogliomas. Methods Forty patients (age 9-61 years) with...
Purpose We explored whether advanced magnetic resonance (MR) imaging techniques could grade oligodendrogliomas. Methods Forty patients (age 9-61 years) with oligodendroglial tumors were selected. There were 23 patients with World Health Organization grade II (group 1) and 17 patients with grade III (group 2) tumors. Apparent diffusion coefficient (ADC) maps were calculated by b values of 0 and 1000 s/mm. Dynamic susceptibility contrast (DSC) images were obtained during the first pass of a bolus of gadolinium-based contrast. These data were post-processed and cerebral blood volume (CBV) maps and permeability (PS) were calculated. MR spectroscopy was acquired after drawing a region of interest on the tumor using two-dimensional chemical shift imaging. Statistical analysis was performed using SPSS software. Results When the rPS was combined with the rCBV, there was a significant difference between the two groups ( p ≤ 0.03) with area under the curve of 0.742 (95% CI: 0.412-0.904). rCBV, rADC, choline/creatine, and choline/NAA alone were able to differentiate between the two groups; however, they did not show any statistical difference with p values of ≤ 0.121, ≤ 0.722, and ≤ 0.582, respectively. A CBV PS product threshold of 0.53 provided a sensitivity of 80% and a specificity of 83.3% in detection of grade III tumors. Conclusion Combined rCBV and rPS can be utilized to grade oligodendrogliomas. ADC values, relative cerebral blood volume (rCBV), and MR spectroscopy alone can be utilized to differentiate between the two groups of oligodendrogliomas but without statistical significance.
Topics: Adolescent; Adult; Area Under Curve; Aspartic Acid; Blood Volume; Brain; Brain Neoplasms; Child; Choline; Creatine; Diffusion Magnetic Resonance Imaging; Humans; Image Interpretation, Computer-Assisted; Magnetic Resonance Spectroscopy; Middle Aged; Neoplasm Grading; Oligodendroglioma; ROC Curve; Young Adult
PubMed: 29469659
DOI: 10.1177/1971400918757217 -
Zhurnal Voprosy Neirokhirurgii Imeni N.... 2017The work explores the molecular genetic features of anaplastic astrocytomas and oligodendrogliomas in a series of 43 cases. The mutational status was studied using...
The work explores the molecular genetic features of anaplastic astrocytomas and oligodendrogliomas in a series of 43 cases. The mutational status was studied using domestic chemicals and reagent kits. We revealed clear genetic differences between astrocytic and oligodendroglial tumors and proposed an algorithm to study diagnostic and prognostic markers.
Topics: Adolescent; Algorithms; Biomarkers, Tumor; Child; Child, Preschool; Female; Humans; Male; Oligodendroglioma
PubMed: 29393283
DOI: 10.17116/neiro201781626-31 -
Science Translational Medicine Dec 2017Investigations into brain function and disease depend on the precise classification of neural cell types. Cells of the oligodendrocyte lineage differ greatly in their...
Investigations into brain function and disease depend on the precise classification of neural cell types. Cells of the oligodendrocyte lineage differ greatly in their morphology, but accurate identification has thus far only been possible for oligodendrocyte progenitor cells and mature oligodendrocytes in humans. We find that breast carcinoma amplified sequence 1 (BCAS1) expression identifies an oligodendroglial subpopulation in the mouse and human brain. These cells are newly formed, myelinating oligodendrocytes that segregate from oligodendrocyte progenitor cells and mature oligodendrocytes and mark regions of active myelin formation in development and in the adult. We find that BCAS1 oligodendrocytes are restricted to the fetal and early postnatal human white matter but remain in the cortical gray matter until old age. BCAS1 oligodendrocytes are reformed after experimental demyelination and found in a proportion of chronic white matter lesions of patients with multiple sclerosis (MS) even in a subset of patients with advanced disease. Our work identifies a means to map ongoing myelin formation in health and disease and presents a potential cellular target for remyelination therapies in MS.
Topics: Animals; Demyelinating Diseases; Humans; Mice; Multiple Sclerosis; Myelin Sheath; Neoplasm Proteins; Oligodendroglia
PubMed: 29212715
DOI: 10.1126/scitranslmed.aam7816 -
Archives of Pathology & Laboratory... Dec 2017- In the recently updated World Health Organization (WHO) classification of central nervous system tumors, our concept of infiltrating gliomas as a molecular dichotomy... (Review)
Review
CONTEXT
- In the recently updated World Health Organization (WHO) classification of central nervous system tumors, our concept of infiltrating gliomas as a molecular dichotomy between oligodendroglial and astrocytic tumors has been codified. Advances in animal models of glioma and a wealth of sophisticated molecular analyses of human glioma tissue have led to a greater understanding of some of the biologic underpinnings of gliomagenesis.
OBJECTIVE
- To review our understanding of gliomagenesis in the setting of the recently updated WHO classification of central nervous system tumors. Topics addressed include a summary of an updated diagnostic schema for infiltrating gliomas, the crucial importance of isocitrate dehydrogenase mutations, candidate cells of origin for gliomas, environmental and other posited contributing factors to gliomagenesis, and the possible role of chromatin topology in setting the stage for gliomagenesis.
DATA SOURCES
- We conducted a primary literature search using PubMed.
CONCLUSIONS
- With multidimensional molecular data sets spanning increasingly larger numbers of patients with infiltrating gliomas, our understanding of the disease at the point of surgical resection has improved dramatically and this understanding is reflected in the updated WHO classification. Animal models have demonstrated a diversity of candidates for glioma cells of origin, but crucial questions remain, including the role of neural stem cells, more differentiated progenitor cells, and glioma stem cells. At this stage the increase in data generated from human samples will hopefully inform the creation of newer animal models that will recapitulate more accurately the diversity of gliomas and provide novel insights into the biologic mechanisms underlying tumor initiation and progression.
Topics: Adult; Animals; Central Nervous System Neoplasms; Chromatin Assembly and Disassembly; Glioma; Humans; Immunohistochemistry; Isocitrate Dehydrogenase; Mice; Mutation; Neoplastic Stem Cells; World Health Organization
PubMed: 29189064
DOI: 10.5858/arpa.2016-0493-RA -
PloS One 2017In the 2016 WHO classification, the diagnosis of oligodendroglioma has been restricted to IDH mutated, 1p19q codeleted tumors (IDHmut-codel). IDHmut oligoastrocytoma is... (Review)
Review
BACKGROUND
In the 2016 WHO classification, the diagnosis of oligodendroglioma has been restricted to IDH mutated, 1p19q codeleted tumors (IDHmut-codel). IDHmut oligoastrocytoma is now classified either as oligodendroglioma or astrocytoma based on presence of 1p19q codeletion. There is growing evidence that this molecular classification more closely reflects patient outcome. Due to the strong association between IDHmut-codel with oligodendroglial morphology, the additional impact of these markers on prognostic accuracy is largely unknown. Our aim was to assess the prognostic impact of IDHmut-codel in an unselected cohort of morphologically classified oligodendroglial tumors.
METHODS
We performed a retrospective chart review of oligodendroglial tumors (WHO grade II and III) operated since 1983. A total of 214 tumors were included, and molecular information was available for 96 tumors. The prognostic impact of IDHmut-codel together with clinical parameters was analyzed by multivariate Cox regression.
RESULTS
IDHmut-codel was registered in 64 tumors while for 150 tumors the molecular profile was negative for IDHmut-codel, unknown or incomplete. Comparison between the two groups showed that patients with IDHmut-codel tumors were younger (42 vs. 48 years), had more frequent frontal tumor location (48 vs. 33%) and presented more often with seizures (72 vs. 51%) and no signs of neurological impairment (14 vs. 30%) than patients harboring tumors with unknown or incomplete molecular profile. Multivariate survival analysis identified young age (HR 1.78 ≥ 40 years), the absence of neurological deficits or personality changes (HR 0.57), frontal tumor location (HR 0.64) and the presence of IDHmut-codel (HR 0.50) as independent predictors for longer survival, whereas tumor grade was not.
CONCLUSION
In this unselected single-institution cohort, the presence of IDHmut-codel was associated with more beneficial clinical parameters and was identified as an independent prognostic factor. We conclude that the classical oligodendroglioma genotype provides additional prognostic data beyond clinical characteristics, morphology and tumor grade.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Brain Neoplasms; Female; Humans; Male; Middle Aged; Oligodendroglioma; Prognosis; Survival Analysis; Young Adult
PubMed: 29186201
DOI: 10.1371/journal.pone.0188419 -
Acta Neuropathologica Jan 2018Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be...
Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification. Furthermore, by additional molecular analyses, we were able to identify pathogenic mutations in BRAF and FGFR1, specific to each group, in a high proportion of cases. Finally, by interrogating our expression data, we were able to show that each molecular group possessed expression phenotypes suggesting different cellular differentiation: astrocytic in one group and oligodendroglial in the second. Informed by this, we were able to identify CCND1, CSPG4, and PDGFRA as immunohistochemical targets which could distinguish between molecular groups. Our data suggest that the current histological classification of glioneuronal tumours does not adequately represent their underlying biology. Instead, we show that there are two molecular groups within glioneuronal tumours. The first of these displays astrocytic differentiation and is driven by BRAF mutations, while the second displays oligodendroglial differentiation and is driven by FGFR1 mutations.
Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Cohort Studies; DNA Methylation; Epilepsy; Female; Ganglioglioma; Gene Expression; Humans; Infant; Male; Mutation; Neoplasms, Neuroepithelial; Phenotype; Proto-Oncogene Proteins B-raf; Receptor, Fibroblast Growth Factor, Type 1
PubMed: 29058119
DOI: 10.1007/s00401-017-1773-z -
EMBO Molecular Medicine Dec 2017Heterozygous mutations in NADP-dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and...
Heterozygous mutations in NADP-dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D-2-hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient-derived xenografts of IDH-mutant versus IDH wild-type glioma to profile the distribution of metabolites at high anatomical resolution This approach was complemented by tracing of labeled nutrients followed by liquid chromatography-mass spectrometry (LC-MS) analysis. Selected metabolites were verified on clinical specimen. Our data identify remarkable differences in the phospholipid composition of gliomas harboring the IDH1 mutation. Moreover, we show that these tumors are characterized by reduced glucose turnover and a lower energy potential, correlating with their reduced aggressivity. Despite these differences, our data also show that D2HG overproduction does not result in a global aberration of the central carbon metabolism, indicating strong adaptive mechanisms at hand. Intriguingly, D2HG shows no quantitatively important glucose-derived label in IDH-mutant tumors, which suggests that the synthesis of this oncometabolite may rely on alternative carbon sources. Despite a reduction in NADPH, glutathione levels are maintained. We found that genes coding for key enzymes in glutathione synthesis are highly expressed in IDH-mutant gliomas and the expression of () correlates with patient survival in the oligodendroglial subtype. This study provides a detailed and clinically relevant insight into the metabolism of IDH1-mutant gliomas and points to novel metabolic vulnerabilities in these tumors.
Topics: Animals; Brain Neoplasms; Carbon Isotopes; Energy Metabolism; Female; Glioma; Humans; Isocitrate Dehydrogenase; Isotope Labeling; Lipid Metabolism; Male; Mice; Mice, Inbred NOD; Mice, SCID; Nitrogen Isotopes; Oxidative Stress; Phospholipids; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Survival Rate; Tumor Cells, Cultured
PubMed: 29054837
DOI: 10.15252/emmm.201707729 -
Acta Neuropathologica Dec 2017Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the...
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.
Topics: Adult; Aged; Aged, 80 and over; Cerebellar Neoplasms; Cerebellum; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Glioma; Humans; Middle Aged
PubMed: 28852847
DOI: 10.1007/s00401-017-1771-1