MicroRNA profiling by array of 8 WHO grade II gliomas and 24 higher grade tumors to identify the molecular determinants of tumor progression
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Barbano R
PROVIDER: S-ECPF-MTAB-1840 | biostudies-other | 2014
REPOSITORIES: biostudies-other
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Project description:Background: Telomerase reverse transcriptase promoter (TERT-p) mutation has been frequently found, but associated with contrary prognosis, in both low-grade gliomas and glioblastomas. For the low-grade gliomas (Grades II-III), TERT-p mutant patients have a better prognosis than the wildtype patients, whereas for the GBMs (Grade IV), TERT-p mutation is related to a poor prognosis. We hypothesize that there exist high-risk patients in LGGs who share GBM-like molecular features, including TERT-p mutation, and need more intensive treatment than other LGGs. A molecular signature is needed to identify these high-risk patients for an accurate and timely treatment. Methods: Using the within-sample relative expression orderings of gene pairs, we identified the gene pairs with significantly stable REOs, respectively, in both the TERT-p mutant LGGs and GBMs but with opposite directions in the two groups. These reversely stable gene pairs were used as the molecular signature to stratify the LGGs into high-risk and low-risk groups. Results: A signature consisting of 21 gene pairs was developed, which can classify LGGs into two groups with significantly different overall survival. The high-risk group has a similar genetic mutation profile and a similar survival profile as GBMs, and these high-risk tumors may progress to a more malignant state. Conclusion: The 21 gene-pair signature based on REOs is capable of identifying high-risk patients in LGGs and guiding the clinical choice for appropriate and timely intervention.
| S-EPMC9047542 | biostudies-literature
Project description:BackgroundHigh-grade gliomas (HGGs) account for 15% of all pediatric brain tumors and are a leading cause of cancer-related mortality and morbidity. Pediatric HGGs (pHGGs) are histologically indistinguishable from their counterpart in adulthood. However, recent investigations indicate that differences occur at the molecular level, thus suggesting that the molecular path to gliomagenesis in childhood is distinct from that of adults. MicroRNAs (miRNAs) have been identified as key molecules in gene expression regulation, both in development and in cancer. miRNAs have been investigated in adult high-grade gliomas (aHGGs), but scant information is available for pHGGs.MethodsWe explored the differences in microRNAs between pHGG and aHGG, in both fresh-frozen and paraffin-embedded tissue, by high-throughput miRNA profiling. We also evaluated the biological effects of miR-17-92 cluster silencing on a pHGG cell line.ResultsComparison of miRNA expression patterns in formalin versus frozen specimens resulted in high correlation between both types of samples. The analysis of miRNA profiling revealed a specific microRNA pattern in pHGG with an overexpression and a proliferative role of the miR-17-92 cluster. Moreover, we highlighted a possible quenching function of miR-17-92 cluster on its target gene PTEN, together with an activation of tumorigenic signaling such as sonic hedgehog in pHGG.ConclusionsOur results suggest that microRNA profiling represents a tool to distinguishing pediatric from adult HGG and that miR-17-92 cluster sustains pHGG.
| S-EPMC3895388 | biostudies-literature
Project description:Background Pediatric low-grade gliomas (pLGGs), particularly incompletely resected supratentorial tumours, can undergo progression after surgery. However to date, there are no predictive biomarkers for progression. Here, we aimed to identify pLGG-specific microRNA signatures and evaluate their value as a prognostic tool. Methods We identified and validated supratentorial incompletey resected pLGG-specific microRNAs in independent cohorts from four European Pediatric Neuro-Oncology Centres. Results These microRNAs demonstrated high accuracy in differentiating patients with or without progression. Specifically, incompletely resected supratentorial pLGGs with disease progression showed significantly higher miR-1248 combined with lower miR-376a-3p and miR-888-5p levels than tumours without progression. A significant (p < 0.001) prognostic performance for miR-1248 was reported with an area under the curve (AUC) of 1.00. We also highlighted a critical oncogenic role for miR-1248 in gliomas tumours. Indeed, high miR-1248 levels maintain low its validated target genes (CDKN1A (p21)/FRK/SPOP/VHL/MTAP) and consequently sustain the activation of oncogenic pathways. Conclusions Altogether, we provide a novel molecular biomarker able to successfully identify pLGG patients associated with disease progression that could support the clinicians in the decision-making strategy, advancing personalized medicine. Supplementary Information The online version contains supplementary material available at 10.1186/s40364-022-00389-x.
| S-EPMC9205050 | biostudies-literature
Project description:ABCB1 belongs to a superfamily of membrane transporters that use ATP hydrolysis to efflux various endogenous compounds and drugs outside the cell. Cancer cells upregulate ABCB1 expression as an adaptive response to evade chemotherapy-mediated cell death. On the other hand, several reports highlight the role of the epigenetic regulation of ABCB1 expression. In fact, the promoter methylation of ABCB1 was found to be methylated in several tumor types, including gliomas, but its role as a biomarker is not fully established yet. Thus, the aim of this study was to analyze the methylation of the ABCB1 promoter in tumor tissues from 50 glioma patients to verify its incidence and to semi-quantitively detect ABCB1 methylation levels in order to establish its utility as a potential biomarker. The results of this study show a high interindividual variability in the ABCB1 methylation level of the samples derived from gliomas of different grades. Additionally, a positive correlation between ABCB1 methylation, the WHO tumor grade, and an IDH1 wild-type status has been observed. Thus, ABCB1 methylation can be regarded as a potential diagnostic or prognostic biomarker for glioma patients, indicating more aggressive tumors.
| S-EPMC9571128 | biostudies-literature
Project description:BackgroundLow-grade gliomas (LGGs) are slow-growing, infiltrative tumors frequently associated with seizures. Predicting which patients will develop early tumor recurrence based on clinical indicators following initial surgical intervention remains a challenge. Seizure recurrence following surgery may be an early indicator of tumor recurrence, especially in patients presenting with increase in seizure frequency.MethodsThis study analyzed 148 patients meeting inclusion criteria (age >18 years, LGG diagnosis, at least 1 seizure event recorded before and after initial surgical intervention). All patients were treated at the Brain and Spine Center at The University of Texas MD Anderson Cancer Center from January 2000 to March 2013. Seizure frequency in a 6-month period before and after tumor resection was categorized as none, 1, few (2 to 3 seizures) or several (>3 seizures). Immediately postoperative seizures (up to 48 hours from surgery) were not included in the analysis.ResultsA total of 116 (78.4%) patients had seizures at initial presentation and most (95%) were started on antiepileptic drugs (AEDs). We found 2 clinical variables with a significant impact on progression-free survival (PFS): Higher seizure frequency during the 6-month postoperative period and seizure frequency increase between the 6-month pre- and the 6-month postoperative periods were both correlated to higher risk of early tumor recurrence (P = .007 and P = .004, respectively).ConclusionSeizure frequency following surgical resection of LGGs and the seizure frequency change between the 6-month preoperative and postoperative periods may serve as clinical predictors of early tumor recurrence in patients with LGGs who are also afflicted by seizures.
| S-EPMC6656314 | biostudies-literature
Project description:miRNAs are small non-coding RNAs frequently altered in human malignancies. They regulate protein-coding gene expression by mediating mRNA degradation and/or repressing translation via the association with the 3’ untranslated region (3’ UTR) of the mRNAs. Aberrant miRNA expression can influence several gene networks and pathways implicated in tumorigenesis and metastasis formation. To reveal miRNAs involved in breast cancer progression we investigated miRNA expression in 77 ductal breast carcinoma biopsies and 17 mammoplasties by microarray analysis. 16 differentially expressed miRNAs were identified comparing patients with or without disease relapse within 72 months from surgery. We have performed a microarray miRNA expression analysis on 77 ductal breast carcinoma biopsies and 17 normal tissues from mammoplastic reductions using the Human Agilent platform (V2). 77 frozen tumor specimens were selected from the Tumor Bank of the Department of Obstetrics and Gynecology, University of Turin. They were obtained from patients who underwent primary surgical treatment between 1988 and 2001 at a median age of 54 years (25-82). Eligibility criteria were the following: diagnosis of invasive breast cancer, all T and N stages, no distant metastasis at diagnosis (M0), complete clinical-pathological data and updated follow up. All patients were treated with radical modified mastectomy or quadrantectomy and axillary dissection plus breast irradiation. As normal breast controls 17 frozen mammoplastic reductions (EPFL, Lausanne) were included in the screening. Appropriate ethical approval was obtained for this study.
| S-ECPF-GEOD-26659 | biostudies-other
Project description:To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.
| S-EPMC6374451 | biostudies-literature
Project description:BackgroundGliomas are diverse neoplasms with multiple molecular subtypes. How tumor-initiating mutations relate to molecular subtypes as these tumors evolve during malignant progression remains unclear.MethodsWe used genetically engineered mouse models, histopathology, genetic lineage tracing, expression profiling, and copy number analyses to examine how genomic tumor diversity evolves during the course of malignant progression from low- to high-grade disease.ResultsKnockout of all 3 retinoblastoma (Rb) family proteins was required to initiate low-grade tumors in adult mouse astrocytes. Mutations activating mitogen-activated protein kinase signaling, specifically KrasG12D, potentiated Rb-mediated tumorigenesis. Low-grade tumors showed mutant Kras-specific transcriptome profiles but lacked copy number mutations. These tumors stochastically progressed to high-grade, in part through acquisition of copy number mutations. High-grade tumor transcriptomes were heterogeneous and consisted of 3 subtypes that mimicked human mesenchymal, proneural, and neural glioblastomas. Subtypes were confirmed in validation sets of high-grade mouse tumors initiated by different driver mutations as well as human patient-derived xenograft models and glioblastoma tumors.ConclusionThese results suggest that oncogenic driver mutations influence the genomic profiles of low-grade tumors and that these, as well as progression-acquired mutations, contribute strongly to the genomic heterogeneity across high-grade tumors.
| S-EPMC5570221 | biostudies-literature
Project description:Purpose of reviewLow-grade gliomas (LGG) are a group of primary brain tumors that arise from supporting glial cells. They are characterized by a mutation in the isocitrate dehydrogenase (IDH) enzyme and include astrocytomas and oligodendrogliomas. They usually affect young adults, and their main treatment consists of surgical resection, followed by radiation and chemotherapy in selected patients. This article reviews recent research on the clinical and molecular aspects of the disease and innovative therapeutic modalities in the process.Recent findingsNewly identified clinical and molecular features are currently used in the classification of LGG and applied in treatment-planning decisions. Advanced studies on the cellular level have an advanced understanding of the metabolic effects induced by IDH mutations, offering opportunities for specific targeted therapies that may improve patient outcomes. Such findings may lead to a paradigm shift in the treatment of these tumors. Although LGG are sensitive to radiation and chemotherapy, these therapies are not curative, and patient survival remains limited, raising the need for more creative and effective interventions.
| S-EPMC7244462 | biostudies-literature
Project description:Low-grade gliomas (LGGs) are a diverse group of primary brain tumors that often arise in young, otherwise healthy patients and generally have an indolent course with longer-term survival in comparison with high-grade gliomas. Treatment options include observation, surgery, radiation, chemotherapy, or a combined approach, and management is individualized based on tumor location, histology, molecular profile, and patient characteristics. Moreover, in this type of brain tumor with a relatively good prognosis and prolonged survival, the potential benefits of treatment must be carefully weighed against potential treatment-related risks. We review in this article current management strategies for LGG, including surgery, radiotherapy, and chemotherapy. In addition, the importance of profiling the genetic and molecular properties of LGGs in the development of targeted anticancer therapies is also reviewed. Finally, given the prevalence of these tumors in otherwise healthy young patients, the impact of treatment on neurocognitive function and quality of life is also evaluated.
| S-EPMC3983820 | biostudies-literature