DNA methylation profiling for molecular classification of adult diffuse lower‑grade gliomas
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ABSTRACT:
PROVIDER: PRJNA734176 | ENA |
REPOSITORIES: ENA
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Project description:DNA methylation profiling has become a powerful tool for neuro-oncology diagnostics. We investigated the value of using DNA methylation profiling to achieve molecular diagnosis in adult primary diffuse lower-grade gliomas according to WHO 2016 classification system of central nervous system tumors. We further evaluated the use of methylation profiling for improved molecular characterization of the tumors and identify prognostic differences beyond histological grade and molecular markers (IDH mutation and 1p/19q codeletion status).
2023-02-27 | GSE175877 | GEO
Project description:Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma (WHO IV), its most malignant subtype, lower-grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notably variable clinical behavior. To examine the foundations of this heterogeneity, we performed multidimensional molecular profiling, including global transcriptional analysis, on 101 lower-grade diffuse astrocytic gliomas collected at our own institution, and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, PDGFRA overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower-grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone (SVZ). This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. In summary, we have elucidated molecularly distinct subclasses of lower-grade diffuse astrocytic glioma that dictate clinical behavior and demonstrate fundamental associations with both IDH mutational status and neuroglial developmental stage. 80 tumor samples, one normal tissue sample (brain)
2012-02-24 | E-GEOD-35158 | biostudies-arrayexpress
Project description:Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma (WHO IV), its most malignant subtype, lower-grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notably variable clinical behavior. To examine the foundations of this heterogeneity, we performed multidimensional molecular profiling, including global transcriptional analysis, on 101 lower-grade diffuse astrocytic gliomas collected at our own institution, and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, PDGFRA overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower-grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone (SVZ). This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. In summary, we have elucidated molecularly distinct subclasses of lower-grade diffuse astrocytic glioma that dictate clinical behavior and demonstrate fundamental associations with both IDH mutational status and neuroglial developmental stage.
2012-02-24 | GSE35158 | GEO
Project description:We have used Illumina Infinium HumanMethylation450 BeadChip array profiling to profile paediatric high grade gliomas and diffuse intrinsic pontine gliomas. The 450K methylation array is being used to separate brain tumour samples on the basis of their methylation profiles which represent the cell of origin the time and place in which tumours arise. Methylation arrays provide data for an integrated molecular diagnosis of brain tumours and define specific molecular subgroups and subtypes of high grade gliomas carrying distinct driver mutations and patterns of somatic alterations. These data form part of an integrated meta-analysis of high grade gliomas in children combining DNA copy number, methylation and high throughput sequencing datasets.
2017-09-28 | E-MTAB-5528 | biostudies-arrayexpress
Project description:This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back (recurrent), progressed, or have not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body’s immune system, and may interfere with the ability of tumor cells to grow and spread.
| 2183538 | ecrin-mdr-crc
Project description:Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but apart from BRAF mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. These tumors are particularly poorly understood. We performed high-resolution copy-number analysis of 44 diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gains, were observed in 28% of diffuse astrocytomas grade II (DA2s) and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene MYB on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged DA2 demonstrated MYBL1 tandem duplication, and few other events. Two novel, truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth when expressed in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.
2013-04-23 | GSE45843 | GEO
Project description:20% of patients affected with diffuse low-grade brain tumors have high cell density foci harboring higher KI67 index and DNA alterations. These foci may represent tumor progression towards high-grade gliomas. Here we performed transcriptome analysis of those foci vs adjacent tumoral tissues dissected from formalin fixed and paraffin embedded blocks.
2020-03-17 | GSE130149 | GEO
Project description:Purpose: More than 90% of children with diffuse intrinsic pontine glioma (DIPG) die within 2 years of diagnosis. There is a dire need to identify therapeutic targets, however lack of patient material for research has limited progress. We evaluated a large cohort of diffuse intrinsic pontine gliomas (DIPGs) to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods: We used single nucleotide polymorphism arrays to evaluate genomic copy number imbalances in 43 DIPGs from 40 patients and in 8 low-grade exophytic brainstem gliomas. Gene expression arrays were used to evaluate expression signatures from 27 DIPGs, 6 low-grade exophytic brainstem gliomas and 66 low-grade gliomas arising outside the brainstem. Results: Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and pediatric glioblastomas outside the brainstem. Focal amplifications of genes within the receptor tyrosine kinase-Ras-PI3-kinase signaling pathway were found in 47% of DIPG, with PDGFRA and MET showing the highest frequency. 30% of DIPG contained focal amplifications of cell-cycle regulatory genes controlling RB phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures relating to developmental processes compared to pediatric glioblastomas arising outside the brainstem, while expression signatures of low-grade exophytic brainstem gliomas were similar to low-grade gliomas outside the brainstem. Copy number analaysis: 43 DIPG samples, 8 Low Grade Gliomas using SNP6.0. Available matched normals are also profiled with SNP6.0. Expression analysis: 29 DIPG samples, 6 Low grade samples Please contact Suzanne Baker at Suzanne.Baker@stjude.org for CEL files and genotype calls.
2011-09-20 | E-GEOD-26576 | biostudies-arrayexpress
Project description:Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but apart from BRAF mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. These tumors are particularly poorly understood. We performed high-resolution copy-number analysis of 44 diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gains, were observed in 28% of diffuse astrocytomas grade II (DA2s) and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene MYB on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged DA2 demonstrated MYBL1 tandem duplication, and few other events. Two novel, truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth when expressed in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas. IRB approval from all institutions was obtained, and all samples were from patients who provided informed consent or were studied with waiver of the requirement for informed consent by the appropriate IRB. Samples of various histologic subtypes were identified and collected at multiple institutions (Boston Children’s Hospital, Boston, MA, The University of Texas School of Medicine Southwestern, Dallas, TX, Children’s Cancer Hospital, Egypt, Cairo, Johns Hopkins University School of Medicine, Baltimore, MD, Children’s National Medical Center, Washington, DC, The Hospital for Sick Children, Toronto, Canada, Mayo Clinic, Rochester, MN). Central histopathologic review was performed by at least three board-certified neuropathologists using WHO criteria. DNA extraction from archival FFPE samples and Array CGH were performed as previously described (Craig, et al., 2012 PLoS One). GC-normalized copy-number data for the samples were then cleaned of known germline CNVs. Circular Binary Segmentation was used to segment the copy-number data, using parameters [alpha=0.001, undo.splits=sdundo, undo.SD=1.5, min.width=5]. Forty-four samples passed QC metrics (based on aCGH quality metrics for DNA integrity) for inclusion in the GISTIC analysis. Segmented data were analyzed with GISTIC 2.0 to determine statistically significant recurrent broad and focal CNAs. The following parameters were used: minimum segment size = 8, lesion amplitude threshold = 0.2, focal/broad cutoff = 0.9x chromosome arm length, q-value threshold 0.10, and gene confidence level 0.95.
2013-04-23 | E-GEOD-45843 | biostudies-arrayexpress
Project description:Purpose: More than 90% of children with diffuse intrinsic pontine glioma (DIPG) die within 2 years of diagnosis. There is a dire need to identify therapeutic targets, however lack of patient material for research has limited progress. We evaluated a large cohort of diffuse intrinsic pontine gliomas (DIPGs) to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods: We used single nucleotide polymorphism arrays to evaluate genomic copy number imbalances in 43 DIPGs from 40 patients and in 8 low-grade exophytic brainstem gliomas. Gene expression arrays were used to evaluate expression signatures from 27 DIPGs, 6 low-grade exophytic brainstem gliomas and 66 low-grade gliomas arising outside the brainstem. Results: Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and pediatric glioblastomas outside the brainstem. Focal amplifications of genes within the receptor tyrosine kinase-Ras-PI3-kinase signaling pathway were found in 47% of DIPG, with PDGFRA and MET showing the highest frequency. 30% of DIPG contained focal amplifications of cell-cycle regulatory genes controlling RB phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures relating to developmental processes compared to pediatric glioblastomas arising outside the brainstem, while expression signatures of low-grade exophytic brainstem gliomas were similar to low-grade gliomas outside the brainstem.
2011-09-21 | GSE26576 | GEO