Glioma Oncogenesis Research Articles

Glioma oncogenesis in the Constitutional mismatch repair deficiency (CMMRD) syndrome.

Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition due to biallelic mutations in one of the mismatch repair (MMR) genes associated with early onset of cancers, especially high-grade gliomas. Our aim was to decipher the molecular specificities of these gliomas. Clinical, histopathological, and whole exome sequencing data were analyzed in 12 children with genetically proven CMMRD and a high-grade glioma. PDL1 expression was present in immunohistochemistry in 50% of the samples. In 9 patients, the glioma harbored an ultra-hypermutated phenotype (104-635 coding single nucleotide variants (SNV) per Mb, median 204). Driver mutations in POLE and POLD1 exonuclease domains were described for 8 and 1 patients respectively and were always present in the mutation burst with the highest variant allele frequency (VAF). The mutational signatures were dominated by MMR-related ones and similar in the different mutation bursts of a same patient without subsequent enrichment of the mutation signatures with POL-driven ones. Median number of coding SNV with VAF above one of the driving polymerase mutation per Mb was 57 (17-191). Our findings suggest that somatic polymerase alterations does not entirely explain the ultra-hypermutant phenotype. SETD2, TP53, NF1, EPHB2, PRKDC, and DICER1 genes were frequently mutated with higher VAF than the deleterious somatic polymerase mutation. CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors.

NDC80/HEC1 promotes macrophage polarization and predicts glioma prognosis via single-cell RNA-seq and invitro experiment.

Glioma is the most frequent and lethal form of primary brain tumor. The molecular mechanism of oncogenesis and progression of glioma still remains unclear, rendering the therapeutic effect of conventional radiotherapy, chemotherapy, and surgical resection insufficient. In this study, we sought to explore the function of HEC1 (highly expressed in cancer 1)in glioma; a component of the NDC80 complex in glioma is crucial in the regulation of kinetochore. Bulk RNA and scRNA-seq analyses were used to infer HEC1 function, and invitro experiments validated its function. HEC1 overexpression was observed in glioma and was indicative of poor prognosis and malignant clinical features, which was confirmed in human glioma tissues. High HEC1 expression was correlated with more active cell cycle, DNA-associated activities, and the formation of immunosuppressive tumor microenvironment, including interaction with immune cells, and correlated strongly with infiltrating immune cells and enhanced expression of immune checkpoints. Invitro experiments and RNA-seq further confirmed the role of HEC1 in promoting cell proliferation, and the expression of DNA replication and repair pathways in glioma. Coculture assay confirmed that HEC1 promotes microglial migration and the transformation of M1 phenotype macrophage to M2 phenotype. Altogether, these findings demonstrate that HEC1 may be a potential prognostic marker and an immunotherapeutic target in glioma.

SETD2 controls m6A modification of transcriptome and regulates the molecular oncogenesis of glioma.

SETD2 is known for its epigenetic regulatory function and a frequently mutated gene in multiple cancers. Recently, it has been inferred that SETD2 regulates m6A mRNA methylation (epitranscriptome) via H3K36me3. The m6A RNA methylation is vital for tumor maintenance, self-renewal, and tumorigenesis. RNA modifications are executed by writers, readers, and erasers. m6A modifiers work along with the molecular cues, H3K36me3, laid down by SETD2. A positive correlation observed between SETD2 and RNA modifiers signifies their direct role in epitranscriptomics. Hence, understanding the epitranscriptomics will provide a new facet for molecular oncogenesis. Glioma is a common, malignant grade IV tumor with limited therapeutic alternatives and a poor prognosis. Yet, its function in glioma is not fully defined.Inthe present study, thorough investigations were done in the m6A RNA methylation regulators expression, the molecular pathways leading to tumor progression, and their respective outcomes in SETD2-mediated RNA methylation. In vitro analysis reveals that SETD2 knockdown positively affected the oncogenic properties of the glioma cell line and a global reduction in m6A levels in the transcriptome. The reduction of m6A in the transcriptome can be attributed to the decreased expression of METTL3 and METTL14. Therefore, we conclude that SETD2-mediated m6A modifications are crucial for glioma oncogenesis.

A noncoding SNP at chromosome 8q24 is implicated in oncogenesis of IDH-mutant gliomas

A noncoding SNP at chromosome 8q24 is implicated in oncogenesis of IDH-mutant gliomas

Identification of cuproptosis-related subtypes and the development of a prognostic model in glioma.

Introduction: A copper-dependent cell death, cuproptosis, involves copper binding with lipoylated tricarboxylic acid (TCA) cycle components. In cuproptosis, ferredoxin 1 (FDX1) and lipoylation act as key regulators. The mechanism of cuproptosis differs from the current knowledge of cell death, which may invigorate investigations into copper's potential as a cancer treatment. An extremely dismal prognosis is associated with gliomas, the most prevalent primary intracranial tumor. In patients with glioma, conventional therapies, such as surgery and chemotherapy, have shown limited improvement. A variety of cell death modes have been confirmed to be operative in glioma oncogenesis and participate in the tumor microenvironment (TME), implicated in glioma development and progression. In this study, we aimed to explore whether cuproptosis influences glioma oncogenesis. Methods: Gene expression profiles related to cuproptosis were comprehensively evaluated by comparing adjacent tissues from glioma tissues in The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/) database. Gene expression, prognostic, clinical, and pathological data of lower-grade gliomas (LGG) and glioblastoma were retrieved from TCGA and Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases. The datasets were managed by "Combat" algorithm to eliminate batch effects and then combined. A consensus clustering algorithm based on the Partitioning Around Medoid (PAM) algorithm was used to classified 725 patients with LGG and glioblastoma multiforme (GBM) into two cuproptosis subtypes. According to the differentially expressed genes in the two cuproptosis subtypes, 725 patients were divided into 2 gene subtypes. Additionally, a scoring system that associated with TME was constructed to predict patient survival and patient immunotherapy outcomes. Furthermore, we constructed a prognostic CRG-score and nomogram system to predict the prognosis of glioma patients. 95 tissue specimens from 83 glioma patients undergoing surgical treatment were collected, including adjacent tissues. Using immunohistochemistry and RT-qPCR, we verified cuproptosis-related genes expression and CRG-score predictive ability in these clinical samples. Results: Our results revealed extensive regulatory mechanisms of cuproptosis-related genes in the cell cycle, TME, clinicopathological characteristics, and prognosis of glioma. We also developed a prognostic model based on cuproptosis. Through the verifications of database and clinical samples, we believe that cuproptosis affects the prognosis of glioma and potentially provides novel glioma research approaches. Conclusion: We suggest that cuproptosis has potential importance in treating gliomas and could be utilized in new glioma research efforts.

HGG-41. Glioma oncogenesis in the constitutional mismatch repair deficiency (CMMRD) syndrome

Abstract PURPOSE: Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS: A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS: Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION: CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.

Circulating miRNAs as Diagnostic and Prognostic Biomarkers in High-Grade Gliomas.

ObjectivesmiR-181a/b and miR-410 downregulation and miR-155 upregulation has been shown to play important roles in the oncogenesis and progression of gliomas including high-grade gliomas. However, the potential role of plasma miR-181a/b, miR-410 and miR-155 in the diagnosis and prognosis of high-grade gliomas remains poorly known.MethodsWe retrieved published articles from the PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science database and obtained different sets of data on microRNAs (miRNAs) expression profiling in glioma and highlighted the most frequently dysregulated miRNAs and their gene-targets (PDCD4, WNT5A, MET, and EGFR) in high-grade gliomas. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was carried out to measure the pre- and postoperative plasma levels of miR-181a/b, miR-410 and miR-155 in 114 Grade 3-4 glioma patients, 77 Grade 1-2 glioma patients and 85 healthy volunteers as control group. The diagnostic and prognostic value of circulating miR-181a/b, miR-410 and miR-155 as biomarker was estimated by the Receiver Operating Characteristic (ROC) curve and the area under the curve (AUC) and Kaplan–Meier analysis.ResultsWe found a plasma miRNA signature including three downexpressed miRNAs and one overexpressed (miR-181a, miR-181b and miR-410; miR-155) in high-grade glioma patients in comparison with low-grade glioma patients control group. The ROC curve AUC of these four circulating miRNAs were ≥ 0.75 for high-grade glioma patients in before and after surgery. Higher circulating miR-155 and lower miR-181a/b and miR-410 expression is associated with clinical data, clinic pathological variables, worse overall survival (OS) of patients and negative correlated with potential gene-targets expression. Moreover, Kaplan–Meier analysis showed that miR-181a/b, miR-410 and miR-155 were independent predictors of OS in high-grade glioma patients.ConclusionsOur data, for the first time, demonstrated that circulating miR-181a/b, miR-410 and miR-155 could be a useful diagnostic and prognostic non-invasive biomarkers in high-grade gliomas.

The metabolomic landscape plays a critical role in glioma oncogenesis.

Cancer cells depend on metabolic reprogramming for survival, undergoing profound shifts in nutrient sensing, nutrient uptake and flux through anabolic pathways, in order to drive nucleotide, lipid, and protein synthesis and provide key intermediates needed for those pathways. Although metabolic enzymes themselves can be mutated, including to generate oncometabolites, this is a relatively rare event in cancer. Usually, gene amplification, overexpression, and/or downstream signal transduction upregulate rate‐limiting metabolic enzymes and limit feedback loops, to drive persistent tumor growth. Recent molecular‐genetic advances have revealed discrete links between oncogenotypes and the resultant metabolic phenotypes. However, more comprehensive approaches are needed to unravel the dynamic spatio‐temporal regulatory map of enzymes and metabolites that enable cancer cells to adapt to their microenvironment to maximize tumor growth. Proteomic and metabolomic analyses are powerful tools for analyzing a repertoire of metabolic enzymes as well as intermediary metabolites, and in conjunction with other omics approaches could provide critical information in this regard. Here, we provide an overview of cancer metabolism, especially from an omics perspective and with a particular focus on the genomically well characterized malignant brain tumor, glioblastoma. We further discuss how metabolomics could be leveraged to improve the management of patients, by linking cancer cell genotype, epigenotype, and phenotype through metabolic reprogramming.

Neurooncology: 2022 update.

This 'Neurooncology: 2022 update' presents topics that were selected by the authors as top ten discoveries published in 2021 in the broader field of neurooncological pathology. This time, the spectrum of topics includes: papers with a direct impact on daily diagnostic practice of CNS tumors in general and with information on how to improve grading of meningiomas; studies shedding new light on the oncogenesis of gliomas (in particular 'optic gliomas' and H3-mutant gliomas); several 'multi-omic' investigations unraveling the intra-tumoral heterogeneity of especially glioblastomas further; a study indicating the potential of 'repurposing' Prozac® for the treatment of glioblastomas; liquid biopsy using CSF for assessment of residual medulloblastoma. In the last part of this review some other papers are mentioned that didn't make it to this (quite subjective) top ten list.

Overexpression of GINS4 is associated with poor prognosis and survival in glioma patients

BackgroundGINS4, an indispensable component of the GINS complex, is vital for a variety of cancer. However, no known empirical research has focused on exploring relationships between GINS4 and glioma. Thus, this study aims to understand and explain the role of GINS4 in glioma.MethodFirst, we used the data in the CGGA, TCGA, GEO, GEPIA, and HPA databases to explore the expression level of GINS4 in glioma, the correlation between GINS4 expression and the clinical features of glioma, its impact on the survival of glioma patients, and verified the analysis results through RT-qPCR, IHC, and meta-analysis. Subsequently, GSEA enrichment analysis is used to find the potential molecular mechanism of GINS4 to promote the malignant process of glioma and the anti-glioma drugs that may target GINS4 screened by CMap analysis. Moreover, we further explored the influence of the GINS4 expression on the immune microenvironment of glioma patients through the TIMER database.ResultsOur results suggested that GINS4 was elevated in glioma, and the overexpression of GINS4 was connected with a vast number of clinical features. The next, GINS4 as an independent prognostic factor, which can result in an unfavorable prognosis of glioma. Once more, GINS4 may be participating in the oncogenesis of glioma through JAK-STAT signaling pathways, etc. 6-thioguanine, Doxazosin, and Emetine had potential value in the clinical application of drugs targeting GINS4. Finally, the expression exhibited a close relationship with some immune cells, especially Dendritic cells.ConclusionGINS4 is an independent prognostic factor that led to a poor prognosis of glioma. The present study revealed the probable underlying molecular mechanisms of GINS4 in glioma and provided a potential target for improving the prognosis of glioma.

Relationship between genetically determined telomere length and glioma risk.

BackgroundTelomere maintenance is increasingly recognized as being fundamental to glioma oncogenesis with longer leukocyte telomere length (LTL) reported to increase risk of glioma. To gain further insight into the relationship between telomere genetics and risk of glioma, we conducted several complementary analyses, using genome-wide association studies data on LTL (78 592 individuals) and glioma (12 488 cases and 18 169 controls).MethodsWe performed both classical and summary Mendelian randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations, we analyzed gene expression and DNA methylation data.ResultsGenetically increased LTL was significantly associated with increased glioma risk, random-effects inverse variance weighted ORs per 1 SD unit increase in the putative risk factor (odds ratio [OR]SD) 4.79 (95% confidence interval: 2.11-10.85; P = 1.76 × 10−4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 × 10−5), 5p15.33 (TERT; PSMR = 9.80 × 10−27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 × 10−5), and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 × 10−4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 × 10−2), 6p21.3 (PSMR = 9.76 × 10−3), 6p22.2 (PSMR = 5.45 × 10−3), 7q31.33 (PSMR = 6.52 × 10−3), and 11q22.3 (PSMR = 8.89 × 10−4) as risk factors for glioma risk. While complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1, and ATM-NPAT1 was implicated in the etiology of glioma.ConclusionsThese observations extend the role of telomere-related genes in the development of glioma.

Circular RNA: A novel type of biomarker for glioma (Review).

With the rapid development of sequencing technologies, the characteristics and functions of circular RNAs (circRNAs) in different tissues, and their underlying pathophysiological mechanisms, have been identified. circRNAs are significantly enriched in the brain and are continually expressed from the embryonic stage to the adult stage in rats. Previous studies have reported that certain circRNAs are differentially expressed in glioma and regulate a number of biological processes, such as cell proliferation, metastasis and oncogenesis of glioma. Furthermore, certain circRNAs have been associated with tumor size, World Health Organization tumor grade and poor prognosis in patients with glioma. It has been hypothesized that circRNAs may be involved in the onset and progression of glioma through transcriptional regulation, protein translation and binding to microRNAs. These properties and functions suggest the potential of circRNAs as prognostic biomarkers and therapeutic targets for glioma. For the present review, published studies were examined from PubMed, Embase, Cochrane Central and the reference lists of the retrieved articles. The aim of the present review was to summarize the progress of circRNA research in glioma, discuss the potential diagnostic and prognostic values, and the roles of circRNAs in glioma, and provide a novel theoretical basis and research concepts for the prediction, diagnosis and treatment of glioma.

Tissue Remodeling and Cell Signaling Underpin Changes in Tumor Microenvironment Heterogeneity in Glioma Oncogenesis

Tissue Remodeling and Cell Signaling Underpin Changes in Tumor Microenvironment Heterogeneity in Glioma Oncogenesis

Linc00475 promotes the progression of glioma by regulating the miR-141-3p/YAP1 axis.

Glioma is the most prevalent and lethal primary brain tumour. Abundant long non‐coding RNAs ( lncRNAs) are aberrant and play crucial roles in the oncogenesis of glioma. The exact functions of linc00475 in glioma remain blurred. Here, we analysed the expression levels of linc00475 by qRT‐PCR and discovered that linc00475 was up‐regulated in glioma and predicted a poor prognosis in patients with glioma. Besides, inhibiting linc00475 restrained the progression of glioma in vitro and in vivo. Further experiments confirmed that linc00475 regulated the progression of glioma by acting as a sponge for miR‐141‐3p. Moreover, we detected the binding sites of linc00475 and miR‐141‐3p, the YAP1‐ 3′UTR and miR‐141‐3p by luciferase reporters. The rescue assays confirmed that inhibiting linc00475 restrained the progression of glioma through the miR‐141‐3p/YAP1 pathway. Collectively, our research demonstrates the key roles of linc00475 in glioma, which could be a promising therapeutic target.

The Role of microRNAs in Gliomas - Therapeutic Implications.

Malignant gliomas constitute a complex disease phenotype that demands optimum decision-making. Despite being the most common type of primary brain tumors, gliomas are highly heterogeneous when their pathophysiology and response to treatment are considered. Such inter-individual variability also renders differential and early diagnosis extremely difficult. Recent evidence highlight that the gene-environment interplay becomes of fundamental importance in oncogenesis and progression of gliomas. To unmask key features of the gliomas disease phenotype and map the inter-individual variability of patients, we explore genotype-to-phenotype associations. Emphasis is put on microRNAs as they regulate gene expression, have been implicated in the pathogenesis of gliomas and may serve as theranostics, empowering non-invasive strategies (circulating free or in exosomes). We mined text and omic datasets (as of 2019) and conducted a mixed-method content analysis. A novel framework was developed to meet the aims of our analysis, interrogating data in terms of content and context. We relied on literature data from PubMed/Medline and Scopus, as they are considered the largest abstract and citation databases of peer-reviewed literature. To avoid selection biases, both publicly available and private texts have been assessed. Both percent agreement and Cohen's kappa statistic have been calculated to avoid biases by SAS® macro MAGREE with multicategorical ratings. Gliomas serve as a paradigm for multifaceted datasets, despite data sparsity and scarcity. miRNAs and miRNA-based therapeutics are ready for prime time. Exosomal miRNAs empower non-invasive strategies, surpassing circulating free miRNAs, when accuracy and precision are considered. miRNAs hold promise as theranostics.

LINC00963 Confers Oncogenic Properties in Glioma by Regulating the miR-506/BCAT1 Axis.

BackgroundGlioma is a prevalent disease of the central nervous system with a high incidence and mortality rate. Many long noncoding RNAs (lncRNAs) have been determined to be critical regulators of glioma oncogenesis. However, the function and mechanism of LINC00963 in glioma have not been fully elucidated.MethodsThe expression level of RNA was determined by qRT-PCR, and the protein level was determined by Western blot analysis. A luciferase activity assay was conducted to verify the interaction between miRNA and lncRNA or the target gene. The proliferation, cell cycle distribution, invasion, and migration were evaluated by MTT, EdU, flow cytometry, wound-healing and Transwell invasion assays, respectively. In vivo tumor growth was evaluated in a xenograft nude mouse model.ResultsWe found that LINC00963 was upregulated in glioma cells and tissues and associated with the poor prognosis of patients with glioma. Ectopic expression of LINC00963 promoted cell proliferation, cell cycle progression, migration, and invasion in vitro and tumorigenesis in vivo. Mechanistically, the results of luciferase activity and RNA pulldown assays validated that LINC00963 could act as a molecular sponge of miR-506. Reciprocal repression was found between LINC00963 and miR-506. In addition, BCAT1 was identified as a target of miR-506, and both the mRNA and protein levels of BCAT1 were reduced by miR-506. In tumor tissues, the expression of BCAT1 was negatively and positively correlated with miR-506 and LINC00963 expression, respectively. The reintroduction of BCAT1 in glioma cells abolished the tumor suppressive function of miR-506 by promoting cell viability and motility. The upregulated LINC00963 and BCAT1 were associated with the aggressive phenotypes of tumors.ConclusionOur data revealed that LINC00963 confers oncogenic function in the progression of glioma and that the LINC00963/miR-506/BCAT1 axis may be a novel mechanism and therapeutic strategy for this disease.

Identification of Dysregulated Competitive Endogenous RNA Networks Driven by Copy Number Variations in Malignant Gliomas.

Gliomas represent 80% of malignant brain tumors. Because of the high heterogeneity, the oncogenic mechanisms in gliomas are still unclear. In this study, we developed a new approach to identify dysregulated competitive endogenous RNA (ceRNA) interactions driven by copy number variation (CNV) in both lower-grade glioma (LGG) and glioblastoma multiforme (GBM). By analyzing genome and transcriptome data from The Cancer Genome Atlas (TCGA), we first found out the protein coding genes and long non-coding RNAs (lncRNAs) significantly affected by CNVs and further determined CNV-driven dysregulated ceRNA interactions by a customized pipeline. We obtained 13,776 CNV-driven dysregulated ceRNA pairs (including 3,954 mRNAs and 306 lncRNAs) in LGG and 262 pairs (including 221 mRNAs and 11 lncRNAs) in GBM, respectively. Our results showed that most of the ceRNA interactions were weakened by CNVs in both LGG and GBM, and many CNV-driven genes shared the same ceRNAs in the dysregulated ceRNA networks. Functional analysis indicated that the CNV-driven ceRNA network involved in some important mechanisms of tumorigenesis, such as cell cycle, p53 signaling pathway and TGF-beta signaling pathway. Further investigation of the ceRNA pairs in the communities from the dysregulated ceRNA network revealed more detailed biological functions related to the oncogenesis of malignant gliomas. Moreover, by exploring the association of CNV-driven ceRNAs with prognosis and histological subtype, we found that the copy number status of MTAP, KLHL9, and ELAVL2 related to the overall survival in LGG and showed high correlation with histological subtype. In conclusion, this study provided new insight into the molecular mechanisms and clinical biomarkers in gliomas.

P14.31 CMV reactivation in a cohort of newly-diagnosed glioblastoma patients treated with temozolomide chemoradiotherapy. A single center analysis

Abstract BACKGROUND The Cytomegalovirus (CMV) is a ubiquitous herpes virus which infects 60–80 % of the population in Europe. Although the CMV usually remains latent, reactivation can occur in the context of an immunodepression, such as low CD4-lymphocyte levels in HIV patients. Glioblastoma (GBM) patients frequently show lymphopenia, which is related to both the immunosuppressive nature of the tumor and to the treatment with concomitant temozolomide (TMZ) and radiotherapy (RT). Surprisingly, the incidence of CMV reactivation in GBM patients has not been clearly studied so far. We report here our experience on CMV reactivation in a cohort of newly-diagnosed GBM patients, treated with RT and TMZ. We assessed the incidence of CMV reactivation in these patients and tried to identify risk factors for such reactivation. MATERIAL AND METHODS All consecutive patients with histologically confirmed malignant GBM recommended for temozolomide chemoradiotherapy in our institution from October 2013 to December 2015 were reviewed. In all patients, sex, age, Karnofsky performance status (KPS), lymphocyte level, serological CMV status and steroid dosages were recorded at the onset, and one month after completion of the concomitant radio-chemotherapy regimen. A CMV reactivation was defined by a detection of CMV DNA > 1000 copies/ml in the patient’s serum. RESULTS 103 patients meeting the analysis criteria were reviewed. Within these 103 patients, 34 patients (33%) had initial negative serology for CMV, and none of them developed a seroconversion after treatment with concomitant RT + TMZ. Among patients with positive IgG (n=69), 16 patients (23%) developed a positive viremia at one point during treatment with concomitant RT + TMZ. Age (>60 years), lymphocyte count before RT (<1500/mm3) and use of steroids were correlated with CMV reactivation (p<0.05 in univariate analysis). A positive CMV viremia during RT+TMZ did not impact the progression free survival (PFS) but was associated with a shorter overall survival (OS) when compared to the others patients (median: 12 months vs 15 months; p=0.04). No clinical symptoms suggestive of CMV infection were reported. CONCLUSION In this single center series, we showed that CMV reactivation occurs in 23% of the GBM patients having a positive serology for CMV. Reactivation was more frequent in older patients, with low lymphocyte counts and treated with steroids. A positive viremia was not associated with poor PFS, a fact that does not support a promoting role of CMV in glioma oncogenesis, which has been sometimes suggested. Yet, the group of patients with CMV reactivation showed a shorter OS, which might be related to an older age and /or poorer clinical conditions in this group.

Overexpression of circular RNA circ-CDC45 facilitates glioma cell progression by sponging miR-516b and miR-527 and predicts an adverse prognosis.

Glioma (GM) is a highly lethal human cancer. Circular RNAs (circRNAs) act as an imperative factor in oncogenesis. We aimed to investigate the biological functions and mechanisms of circ-CDC45 in GM. circ-CDC45 expression in GM specimens and cell lines was measured by real-time quantitative reverse transcription polymerase chain reaction. Fisher's exact test and Kaplan-Meier curves further analyzed its clinical implications. A gain/loss-of-function study was conducted to investigate the role of circ-CDC45 in GM. Additionally, luciferase reporter and rescue assays were performed to unravel the mechanisms of circ-CDC45. High circ-CDC45 expression was found in GM specimens and cells, which was tightly related to a larger tumor size, higher world health organization (WHO) stages, and worse survival for patients with GM. Functionally, manipulation of circ-CDC45 expression strongly affected cell growth, apoptosis, migration and invasion, which suggests the oncogenic function of circ-CDC45 in GM oncogenesis. Stepwise mechanism studies indicated that circ-CDC45 sponged and regulated the expression of miR-516b and miR-527 to promote cell growth and invasion. Briefly, the regulatory network of circ-CDC45/miR-516b/miR-527 plays a pivotal role in GM tumorigenesis and may act as a potential target for GM treatment.

GATAD1 gene amplification promotes glioma malignancy by directly regulating CCND1 transcription.

BackgroundThe GATAD1 gene overexpression induced by GATAD1 amplification upregulation is detected in different human tumors. To date, the relationship between GATAD1 amplification and glioma oncogenesis and malignancy is still unknown.MethodsGATAD1 gene amplification and expression were analyzed in 187 gliomas using qPCR and immunostaining. The relation of GATAD1 to patients’ prognoses was assessed via the Kaplan–Meier method. The MTT and orthotopic tumor transplantation assays were used to identify the function of GATAD1 in glioma proliferation. cDNA microarray, ChIP qPCR, EMSA and 3C were used to screen the downstream mechanism of GATAD1 regulating glioma proliferation.ResultsOur results indicated that GATAD1 gene amplification and GATAD1 gene expression are novel independent diagnosis biomarkers to indicate poor outcome of glioma patients. GATAD1 knockdown can remarkably suppress GBM cell proliferation both in vitro and in vivo. GATAD1 could promote CCND1 gene transcription by inducing long range chromatin architectural interaction on the CCND1 promoter. Then GATAD1 sequentially accelerates GBM cell cycle transition and proliferation via regulating CCND1.ConclusionsWe identify GATAD1 as a novel potential diagnosis biomarker and promising prognosis predictor in glioma patients. Functionally, we confirm GATAD1 as an epigenetic chromatin topological regulator that promotes glioma proliferation by targeting CCND1.