Early postoperative treatment versus initial observation in CNS WHO grade 2 and 3 oligodendroglioma: clinical outcomes and DNA methylation patterns
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PROVIDER: PRJNA861278 | ENA |
REPOSITORIES: ENA
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Project description:In the past decades, ample evidence has shown that combined radio-chemotherapy is superior to either radiotherapy or chemotherapy alone in oligodendroglioma. However, the survival benefit comes at the cost of immediate and long-term toxicities. Therefore, deferring postoperative therapy until progression may be a valid option to delay treatment-related side effects. Still, systematic data and reliable predictive biomarkers are limited. In this large retrospective series of oligodendroglioma cases, we could show that early postoperative treatment is not associated with improved PFS and OS while correcting for baseline differences between both groups. In addition, we performed whole-genome DNA methylation analyses and observed a predictive role of certain methylation patterns independent from MGMT promoter methylation status, extent of resection and CNS WHO grade. The results of this real-life study may serve as a benchmark for future trial planning in oligodendroglioma, and further studies should evaluate the predictive value of DNA methylation profiles.
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Project description:Oligodendroglioma driver mutations are known, yet signature slow growth rates of these glial tumours are poorly understood. Here we show using patient biopsies that neoplastic and non-neoplastic cells in the tumour mass display elevated ERK signaling, proliferate ectopically, and undergo cell death. Oligodendroglioma cell cross-talk with the tumour microenvironment is mediated partly by extracellular vesicles, which inhibit astrocyte expansion in vitro. Elevated extracellular vesicle biogenesis gene (SMPD3,TSG101) expression positively correlates with longer patient survival. Accordingly, SMPD3 and TSG101 knock-down enhances oligodendroglioma cell expansion whereas overexpression slows cell growth. SMPD3 knock-down also enhances oligodendroglioma growth in cortical xenografts and in human cerebral organoids. Shared signature features of ODG cell line-derived vesicular proteomes include ribosomal biogenesis proteins, whereas the soluble secretome is growth factor-rich, the pro-proliferative effects of which are blocked by foretinib. Oligodendroglioma cell growth is thus controlled by the combined effects of cytostatic/cytotoxic extracellular vesicles and soluble pro-proliferative growth factors.
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Project description:WHO classification for tumors of the central nervous system strongly endorses molecular tests for the precise diagnosis of diffuse gliomas. While alterations in the DNA methylation status of gliomas are already well documented and used in specialised clinical centers to distinguish between brain tumor entities, changes to the epigenetic layer at the level of histone modifications are only poorly characterised. Here, we applied a recently developed data-independent acquisition (DIA) - mass spectrometry method to generate a comprehensive histone epi-proteomic map that documents the abundance of almost all characterized and many uncharacterized histone modifications to a series of IDH-mutant oligodendroglioma and astrocytoma samples. Our analysis documented significant abundance differences in almost one-third of the 144 quantified histone peptides. Among them are lower abundance levels of the polycomb repressive mark H3K27me3 in oligodendroglioma samples compared to astrocytomas. We validated this finding by immunohistochemistry using the C36B11 antibody. Surprisingly, we observed inconsistencies with another widely applied H3K27me3 antibody (07-449), providing a warning flag for immunohistochemistry of brain cancers. An unbiased unsupervised clustering analysis of the proteomic dataset separated the two IDH-mutant glioma subtypes in full accordance to the EPIC DNA methylation classifier and the 1p/19q status. The clustering also revealed at least two histone epi-proteomic subgroups of oligodendroglioma, a feature not observable in the DNA methylation dataset. Our results indicate that histone epi-proteomic profiling at the depth of the current method has the capacity to identify clinically-relevant glioma sub-groups. In addition to being of use for diagnostic purposes, this could also provide novel insights in glioma biology and may identify new therapeutic targets.
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Project description:Oligoastrocytoma (OA) was formerly defined as a mixed glioma exhibiting histological features of both astrocytoma and oligodendroglioma. However, OA has been shown to be attributable to either glioma-type based on its molecular characteristics and was excluded from the glioma classification with the introduction of the integrated diagnosis. Nevertheless, some cases showing genetic features of both oligodendroglioma and astrocytoma have been reported since the integrated diagnosis era, and whether OA exists as a glioma-type remains controversial. All previously reported cases were mixed gliomas with and without 1p/19q-codeletion in the lineage of isocitrate dehydrogenase (IDH) mutant gliomas. Herein, we described a 33-year-old man with a progressive headache. Magnetic resonance imaging showed a large left frontal lobe tumor composed of a cystic component with contrast-enhancing walls and a non-contrast-enhancing solid component. The patient underwent a gross total removal of the tumor. Histologically, the cystic and solid components showed oligodendroglioma and astrocytoma morphology, respectively. Immunohistochemically, IDH1-R132H staining was positive in the cystic component and negative in the solid component. Sanger sequencing confirmed the IDH1-R132H mutation and the C228T mutation in the telomerase reverse transcriptase promoter (TERTp) region in the cystic component, while both IDH1/2 and TERTp were wildtype in the solid component. Fluorescence in situ hybridization revealed 1p/19q-codeletion in both areas. The integrated diagnosis led to the diagnosis of oligoastrocytoma consisting of IDH-mutant 1p/19q-codeleted oligodendroglioma and IDH-wildtype astrocytoma. Furthermore, deoxyribonucleic acid (DNA) extracted separately from each area of formalin-fixed paraffin-embedded specimen revealed a distinct methylation profile. On the other hand, the global DNA copy-number analysis derived from the microarray data showed similar copy-number profiles including 1p/19q-codeletion for both sites. This is the first report of a dual-genotype oligoastrocytoma with IDH-mutant 1p/19q-codeleted oligodendroglioma and IDH-wildtype astrocytoma. This extremely rare case provides profound insight into the process of acquiring genetic abnormalities in the development of glioma.
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Project description:Oligodendroglioma is a primary central nervous system tumor classified by the presence of isocitrate dehydrogenase (IDH) mutations and codeletion of 1p/19q. Here we describe the generation of an IDH-mutant 1p/19q-codeleted oligodendroglioma mouse model using in utero electroporation. We identified IDH1R132H, PIK3CAE545K, CicKO, Fubp1KO and Cdkn2aKO as the optimal combination (termed OligoCdkn2a) to drive fully penetrant tumors that histologically resemble human grade II/III IDH-mutant, 1p/19q-codeleted oligodendroglioma. Replacing Cdkn2a with Trp53 loss in this mouse model shifted tumor histology towards high grade astrocytoma. OligoCdkn2a tumors displayed metabolic and transcriptional changes associated with IDH and CIC mutations, and single cell sequencing identified a bias towards oligodendrocyte differentiation compared to an IDH wild-type glioblastoma mouse model. OligoCdkn2a tumors represent the first mouse model system to recapitulate the genetic, histological and transcriptional features of human IDH-mutant 1p/19q-codeleted oligodendrogliomas, offering a platform to further dissect tumor biology and test new therapeutic strategies.
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Project description:Oligodendroglioma is a primary central nervous system tumor classified by the presence of isocitrate dehydrogenase (IDH) mutations and codeletion of 1p/19q. Here we describe the generation of an IDH-mutant 1p/19q-codeleted oligodendroglioma mouse model using in utero electroporation. We identified IDH1R132H, PIK3CAE545K, CicKO, Fubp1KO and Cdkn2aKO as the optimal combination (termed OligoCdkn2a) to drive fully penetrant tumors that histologically resemble human grade II/III IDH-mutant, 1p/19q-codeleted oligodendroglioma. Replacing Cdkn2a with Trp53 loss in this mouse model shifted tumor histology towards high grade astrocytoma. OligoCdkn2a tumors displayed metabolic and transcriptional changes associated with IDH and CIC mutations, and single cell sequencing identified a bias towards oligodendrocyte differentiation compared to an IDH wild-type glioblastoma mouse model. OligoCdkn2a tumors represent the first mouse model system to recapitulate the genetic, histological and transcriptional features of human IDH-mutant 1p/19q-codeleted oligodendrogliomas, offering a platform to further dissect tumor biology and test new therapeutic strategies.
2026-04-15 | GSE326990 | GEO
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Project description:Treatment options and reliable predictive marker to determine patients at risk to develop postoperative LD and to define the optimal time point of liver resection are limited. Accordingly, there is an urgent need for an easily assessable preoperative test to predict postoperative liver function recovery, specifically as current markers are often expensive, time consuming and sometimes invasive. Emerging evidence suggests that microRNA (miRNA) signatures represent potent diagnostic, prognostic and treatment response biomarkers for several diseases. Using next-generation sequencing as an unbiased systematic approach 554 miRNAs were detected in preoperative plasma of 21 patients suffering from postoperative LD after liver resection and 27 matched controls. Subsequently, we identified a miRNA signature - consisting of miRNAs 151a-5p, 192-5p and 122-5p - that highly correlated with patients developing postoperative LD after liver resection. The predictive potential for postoperative LD was subsequently confirmed using real-time PCR in an independent validation cohort of 98 patients. Ultimately, a regression model of the two miRNA ratios 151a-5p to 192-5p and 122-5p to 151a-5p was found to reliably predict postoperative LD, severe morbidity, prolonged intensive care unit and hospital stay and even mortality prior to surgery with a remarkable accuracy, thereby outperforming established markers of postoperative LD. Ultimately, we documented that miRNA ratios closely followed liver function recovery after partial hepatectomy. Conclusion: Given the clinical relevance of predicting potentially fatal postoperative clinical outcome after liver resection, our data demonstrate the clinical utility of a novel miRNA-based biomarker to support the selection of patients undergoing partial hepatectomy. The dynamical changes during liver function recovery indicate a possible role in tailoring the optimal time point of surgery to each individual patient. Thereby, our data might help to tailor surgical strategies to the specific risk profile of individual patients.
2019-06-30 | GSE123605 | GEO