Methylation data from cerebral tumors of WHO grade II and III
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE129477 | GEO | 2019/05/09
REPOSITORIES: GEO
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Project description:Low grade gliomas (LGG; WHO grade 2 astrocytomas, oligodendrogliomas and oligoastrocytomas) account for about 25% of diffuse gliomas. Most occur in young adults between the ages of 30 and 45 years, and are usually only diagnosed after a seizure. In general, they can be characterised by a long period of continuous slow growth, followed by malignant transformation that will be the cause of death up to 25 years after onset. However, there is a significant number of patients for whom malignant progression is more rapid, with mortality observed within 5 years. This suggests that, as with other tumour types, there may be different subtypes of LGG with specific prognosis. It follows that being able to identify these subtypes may permit better patient stratification and aid targeted treatments. Until recently, our understanding of the variables involved in patient prognosis included the type of tumour oligodendroglial tumours indicate better prognosis than oligoastrocytic or astrocytic and presence of the 1p-19q co-deletion. In addition, the recent discovery of mutations in IDH1&2 in the majority of LGGs provided another means of stratifying patients, while offering an important insight into their biology. However, we still understand very little of the biology behind the genesis and progression of the 70-80% of LGG that bear IDH1&2 mutations, let alone the remaining IDH wild-type tumours.
2015-07-07 | E-MTAB-3708 | biostudies-arrayexpress
Project description:Treatment modalities for patients with low grade glioma (LGG) WHO grade II are controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk adjusted treatments are required to preserve cognitive function and quality of life. We aim at identifying mechanisms and associated molecular markers predicting benefit from radiotherapy (RT) or temozolomide (TMZ) on progression free survival in 120 isocitrate dehydrogenase 1 or 2 (IDHmt) mutant LGG treated in the randomized phase III trial EORTC 22033. IDH mutations, the characteristic hallmark of LGG, are associated with a CpG island methylator phenotype (CIMP). Given the genotoxic treatments in this study we determined the DNA methylome of DNA damage response (DDR) genes and assessed the association with progression free survival (PFS). We identified 62 functional CpGs corresponding to 24 of 410 DDR genes in the multidimensional LGG dataset from The Cancer Genome Atlas. Despite the low-powered study, the simulations suggested that seven CpGs, associated with 4 genes could be predictive for PFS in EORTC 22033. Most interestingly, two of the CpGs correspond to MGMT and consisted of the 2 probes used in the MGMT-STP27 classifier. The extent of methylation was predictive for PFS in the TMZ, but not the RT arm. LGG IDHmt and 1p and 19q codeleted that overlap largely with oligodendroglioma displayed a higher extent of MGMT methylation than the IDHmt non-codeleted tumors based on several independent LGG datasets. This is consistent with a better PFS of codeleted patients in the TMZ arm as compared to the non-codeleted patients, while no difference was observed in the RT-arm.
2018-01-31 | GSE104293 | GEO
Project description:Gliomas are immunologically cold tumors that can be broken into several categories based on either RNA expression profiles or methylation profiles, with isocitrate dehydrogenase (IDH) mutations defining a major segregration between types. IDH mutant gliomas often exhibit defects in the retinoic acid pathway. We treated mice harboring IDH mutant gliomas with all-trans retinoic acid, and found that this treatment cause reductions in tumor growth and a swith in immune profiles in the tumor microenvironment.
2024-04-19 | GSE172387 | GEO
Project description:Background. We aimed to develop a gene expression-based prognostic signature for isocitrate dehydrogenase (IDH) wild-type glioblastoma using clinical trial datasets representative of glioblastoma clinical trial populations. Results. NanoString data were available from 512 patients in the discovery ATE dataset. Elastic net identified a prognostic signature of nine genes (CHEK1, GPR17, IGF2BP3, MGMT, MTHFD1L, PTRH2, SOX11, S100A9, and TFRC). Translating weighted elastic net scores to an average z-score signature conserved the prognostic value of the ATE signature. The z-score signature was prognostic for OS in the ATE dataset (P < 0.0001), as expected, and in the validation cohorts (AVAglio, P < 0.0001; GLARIUS, P = 0.021; UCLA, P = 0.0037). The signature remained prognostic following adjustment for MGMT promoter methylation status or corticosteroid use at baseline. A positive correlation between the signature and proneural/proliferative subtypes was observed in patients with MGMT non-methylated promoter status. Conclusions. The ATE signature showed prognostic value and may enable clinical trial stratification for IDH wild-type glioblastoma.
2020-06-01 | GSE150614 | GEO
Project description:Background. We aimed to develop a gene expression-based prognostic signature for isocitrate dehydrogenase (IDH) wild-type glioblastoma using clinical trial datasets representative of glioblastoma clinical trial populations. Results. NanoString data were available from 512 patients in the discovery ATE dataset. Elastic net identified a prognostic signature of nine genes (CHEK1, GPR17, IGF2BP3, MGMT, MTHFD1L, PTRH2, SOX11, S100A9, and TFRC). Translating weighted elastic net scores to an average z-score signature conserved the prognostic value of the ATE signature. The z-score signature was prognostic for OS in the ATE dataset (P < 0.0001), as expected, and in the validation cohorts (AVAglio, P < 0.0001; GLARIUS, P = 0.021; UCLA, P = 0.0037). The signature remained prognostic following adjustment for MGMT promoter methylation status or corticosteroid use at baseline. A positive correlation between the signature and proneural/proliferative subtypes was observed in patients with MGMT non-methylated promoter status. Conclusions. The ATE signature showed prognostic value and may enable clinical trial stratification for IDH wild-type glioblastoma.
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Project description:Background. We aimed to develop a gene expression-based prognostic signature for isocitrate dehydrogenase (IDH) wild-type glioblastoma using clinical trial datasets representative of glioblastoma clinical trial populations. Results. NanoString data were available from 512 patients in the discovery ATE dataset. Elastic net identified a prognostic signature of nine genes (CHEK1, GPR17, IGF2BP3, MGMT, MTHFD1L, PTRH2, SOX11, S100A9, and TFRC). Translating weighted elastic net scores to an average z-score signature conserved the prognostic value of the ATE signature. The z-score signature was prognostic for OS in the ATE dataset (P < 0.0001), as expected, and in the validation cohorts (AVAglio, P < 0.0001; GLARIUS, P = 0.021; UCLA, P = 0.0037). The signature remained prognostic following adjustment for MGMT promoter methylation status or corticosteroid use at baseline. A positive correlation between the signature and proneural/proliferative subtypes was observed in patients with MGMT non-methylated promoter status. Conclusions. The ATE signature showed prognostic value and may enable clinical trial stratification for IDH wild-type glioblastoma.
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Project description:Background. We aimed to develop a gene expression-based prognostic signature for isocitrate dehydrogenase (IDH) wild-type glioblastoma using clinical trial datasets representative of glioblastoma clinical trial populations. Results. NanoString data were available from 512 patients in the discovery ATE dataset. Elastic net identified a prognostic signature of nine genes (CHEK1, GPR17, IGF2BP3, MGMT, MTHFD1L, PTRH2, SOX11, S100A9, and TFRC). Translating weighted elastic net scores to an average z-score signature conserved the prognostic value of the ATE signature. The z-score signature was prognostic for OS in the ATE dataset (P < 0.0001), as expected, and in the validation cohorts (AVAglio, P < 0.0001; GLARIUS, P = 0.021; UCLA, P = 0.0037). The signature remained prognostic following adjustment for MGMT promoter methylation status or corticosteroid use at baseline. A positive correlation between the signature and proneural/proliferative subtypes was observed in patients with MGMT non-methylated promoter status. Conclusions. The ATE signature showed prognostic value and may enable clinical trial stratification for IDH wild-type glioblastoma.
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Project description:A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation towards the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.
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Project description:More than 50% of patients with chondrosarcomas exhibit gain-of-function mutations in either isocitrate dehydrogenase 1 (IDH1) or IDH2. In this study, we performed genome-wide CpG methylation sequencing of chondrosarcoma biopsies and found that IDH mutations were associated with DNA hypermethylation at CpG islands but not other genomic regions. Regions of CpG island hypermethylation were enriched for genes implicated in stem cell maintenance/differentiation and lineage specification. In murine 10T1/2 mesenchymal 20 progenitor cells, expression of mutant IDH2 led to DNA hypermethylation and an impairment in differentiation that could be reversed by treatment with DNA-hypomethylating agents. Introduction of mutant IDH2 also induced loss of contact inhibition and generated undifferentiated sarcomas in vivo. The oncogenic potential of mutant IDH2 correlated with the ability to produce 2-hydroxyglutarate. Together, these data demonstrate that neomorphic IDH2 mutations can be oncogenic in mesenchymal cells.. RRBS sequencing of (1) IDH wild type and mutant human chondrosarcomas, (2) isogenic cell lines expressing wild-type or mutant IDH.
2013-10-21 | E-GEOD-50539 | biostudies-arrayexpress
Project description:Glioblastoma is the most common malignant primary brain tumor. Clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNA (lncRNA) alterations may contribute to glioblastoma pathogenesis and potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was analyzed in multiple glioblastoma gene expression data sets for associations with prognosis and IDH mutation and MGMT promoter methylation status. The role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, less invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses and determination of reactive oxygen species (ROS) levels revealed impaired mitochondrial function and increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2) as a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
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