Prognostic Marker For Glioma Research Articles

White Matter Integrity of the Corticospinal Tract for Estimation of Individual Patient Risk for Postoperative Neurological Deterioration after Glioma Surgery.

Tractography has become a standard tool for planning neurosurgical operations and has been proven to be useful for risk stratification. In various conditions, tractography-derived white matter integrity has been shown to be associated with neurological outcome. Postoperative performance has been shown to be a prognostic marker in glioma. We aimed to assess the relation of preoperative corticospinal tract (CST) integrity with postoperative neurological deterioration in patients with malignant glioma. We retrospectively analyzed a cohort of 24 right-handed patients (41.7% female) for perioperative neurological performance score (NPS) and applied our anatomical tractography workflow to extract the median fractional anisotropy (FA) of the CST in preoperative magnetic resonance imaging (MRI). Median FA of the CST ipsilateral to the tumor correlated significantly with preoperative NPS (p = 0.025). After rank order correlation and multivariate linear regression, we found that the preoperative median FA of the right CST correlates with preoperative NPS, independently from epidemiological data (p = 0.019). In patients with lesions of the right hemisphere, median FA of the right CST was associated with a declining NPS in multivariate linear regression (p = 0.024). Receiver operating characteristic (ROC) analysis revealed an optimal FA cutoff at 0.3946 in this subgroup (area under the curve 0.83). Patients below that cutoff suffered from a decline in neurological performance significantly more often (p = 0.020). Assessment of preoperative white matter integrity may be a promising biomarker for risk estimation of patients undergoing craniotomy for resection of malignant glioma.

Identification of the novel prognostic biomarker, MLLT11, reveals its relationship with immune checkpoint markers in glioma.

AimThis study aimed to explore the expression pattern of MLLT11 under different pathological features, evaluate its prognostic value for glioma patients, reveal the relationship between MLLT11 mRNA expression and immune cell infiltration in the tumor microenvironment (TME), and provide more evidence for the molecular diagnosis of glioma and immunotherapy.MethodsUsing large-scale bioinformatic approach and RNA sequencing (RNA-seq) data from public databases The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and The Gene Expression Omnibus (GEO)), we investigated the relationship between MLLT11 mRNA levels and pathologic characteristics. The distribution in the different subtypes was observed based on Verhaak bulk and Neftel single-cell classification. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for bioinformatic analysis. Kaplan–Meier survival analysis and Cox regression analysis were used for survival analysis. Correlation analyses were performed between MLLT11 expression and 22 immune cells and immune checkpoints in the TME.ResultsWe found that MLLT11 expression is decreased in high-grade glioma tissues; we further verified this result by RT­PCR, Western blotting, and immunohistochemistry using our clinical samples. According to the Verhaak classification, high MLLT11 expression is mostly clustered in pro-neutral (PN) and neutral (NE) subtypes, while in the Neftel classification, MLLT11 mainly clustered in neural progenitor-like (NPC-like) neoplastic cells. Survival analysis revealed that low levels of MLLT11 expression are associated with a poorer prognosis; MLLT11 was identified as an independent prognostic factor in multivariate Cox regression analyses. Functional enrichment analyses of MLLT11 with correlated expression indicated that low MLLT11 expression is associated with the biological process related to the extracellular matrix, and the high expression group is related to the synaptic structure. Correlation analyses suggest that declined MLLT11 expression is associated with increased macrophage infiltration in glioma, especially M2 macrophage, and verified by RT­PCR, Western blotting, and immunohistochemistry using our clinical glioma samples. MLLT11 had a highly negative correlation with immune checkpoint inhibitor (ICI) genes including PDCD1, PD-L1, TIM3(HAVCR2), and PD‐L2 (PDCD1LG2).Conclusion MLLT11 plays a crucial role in the progression of glioma and has the potential to be a new prognostic marker for glioma.

Analysis and Validation of TMED3 correlates with poor prognosis and tumor immune infiltration of glioma.

Glioma is the most common primary intracranial tumor. It is notorious for its high degree of malignancy, strong invasion, and poor prognosis. The transmembrane emp24 trafficking protein 3 (TMED3) belongs to the TMED family, which is responsible for intracellular protein transport and innate immune signal transmission. More and more evidence shows that TMED3 plays a key role in the tumor progression of human cancer. However, the role and potential molecular mechanism of TMED3 in glioma have not been clarified. TMED3 expression levels, clinical data, survival prognosis, prediction of upstream miRNA, and immune-related analyses were all analyzed utilizing relevant databases. Finally, a molecular cell experiment confirmed TMED3 expression in glioma. We discovered that TMED3 is overexpressed in most tumors, including gliomas, and is associated with tumor staging and prognosis. Subsequently, a combination of a series of bioinformatics analyses, including correlation and survival analyses, identified miR-1296-5p as the most potent upstream miRNA of TMED3 in gliomas.Additionally, we analyzed the relationship between TMED3 level and tumor immune cell infiltration and immune checkpoint expression. TMED3 is highly expressed in gliomas and is associated with tumor staging and affects the prognosis of patients. Therefore, the TMED3 gene may be a potential immunotherapy target and prognostic marker for gliomas.

PDPN marks a subset of aggressive and radiation-resistant glioblastoma cells.

Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs). Clonogenic assays and xenograft experiments revealed that PDPN expression was associated with radiotherapy resistance and tumor aggressiveness. We further demonstrate that knockdown of PDPN in GSCs in vivo is sufficient to improve overall survival in an intracranial xenograft mouse model. PDPN therefore identifies a subset of aggressive, treatment-resistant glioma cells responsible for radiation resistance and may serve as a novel therapeutic target.

Hypomethylation-induced prognostic marker zinc finger DHHC-type palmitoyltransferase 12 contributes to glioblastoma progression.

BackgroundGlioma is the most common intracranial primary malignancy, characterized by abnormal signal transductions caused by transcriptional and post-transcriptional regulators. Studies show the palmitoylation of oncoproteins and tumor suppressors participate in cancer progression, while studies of protein S-palmitoyltransferases in glioma are limited. A systematic analysis of zinc finger DHHC-type palmitoyltransferases (ZDHHC) in glioma is still lacking.MethodsA prognostic heatmap and Kaplan-Meier overall survival plot of 24 members of the ZDHHC family in pan-cancer created. The expression and prognostic significance of ZDHHC12 was analyzed by using Gene Expression Profiling Interactive Analysis (GEPIA) and PrognoScan. DBTRG and U251 cells with silenced ZDHHC12 expression were constructed and used for cell counting kit-8 (CCK-8), Transwell assay and wound healing assay in vitro.ResultsHere, we first conducted expression and prognostic analyses of 24 ZDHHCs from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and other glioma datasets. We found ZDHHC12 to be the only unfavorable prognostic marker in glioma. The function of ZDHHC12 in glioma was then investigated with loss-of-function strategies and in vitro cell assays. Results showed that ZDHHC12 knockdown remarkably reduced the growth, migration, and invasion capabilities in DBTRG and U251 cell lines, suggesting that ZDHHC12 may contribute to malignant behavior in glioma cells. Finally, the molecular basis for ZDHHC12 expression in glioma was analyzed, and DNA hypomethylation was found to be responsible for increased ZDHHC12 mRNA expression and related prognoses.ConclusionsZDHHC12 positively promoted the proliferation and migration of glioma cells. Decreased DNA methylation may lead to increased ZDHHC12 expression in gliomas. This study may deepen the understanding of glioma progression and therapeutics.

SMAGP is a Prognostic Marker for Glioma and is Associated with Tumor Metabolism

SMAGP is a Prognostic Marker for Glioma and is Associated with Tumor Metabolism

Value of long non-coding RNA HAS2-AS1 as a diagnostic and prognostic marker of glioma

BackgroundGlioma presents high incidence and poor prognosis, and therefore more effective treatments are needed. Studies have confirmed that long non-coding RNAs (lncRNAs) basically regulate various human diseases including glioma. It has been theorized that HAS2-AS1 serves as an lncRNA to exert an oncogenic role in varying cancers. This study aimed to assess the value of lncRNA HAS2-AS1 as a diagnostic and prognostic marker for glioma. MethodsThe miRNA expression data and clinical data of glioma were downloaded from the TCGA database for differential analysis and survival analysis. In addition, pathological specimens and specimens of adjacent normal tissue from 80 patients with glioma were used to observe the expression of HAS2-AS1. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic ability and prognostic value of HAS2-AS1 in glioma. Meanwhile, a Kaplan–Meier survival curve was plotted to evaluate the survival of glioma patients with different HAS2-AS1 expression levels. ResultsHAS2-AS1 was significantly upregulated in glioma tissues compared with normal tissue. The survival curves showed that overexpression of HAS2-AS1 was associated with poor overall survival (OS) and progression-free survival (PFS). Several clinicopathological factors of glioma patients, including tumor size and WHO grade, were significantly correlated with HAS2-AS1 expression in tissues. The ROC curve showed an area under the curve (AUC) value of 0.863, indicating that HAS2-AS1 had good diagnostic value. The ROC curve for the predicted OS showed an AUC of 0.906, while the ROC curve for predicted PFS showed an AUC of 0.88. Both suggested that overexpression of HAS2-AS1 was associated with poor prognosis. ConclusionsNormal tissues could be clearly distinguished from glioma tissues based on HAS2-AS1 expression. Moreover, overexpression of HAS2-AS1 indicated poor prognosis in glioma patients. Therefore, HAS2-AS1 could be used as a diagnostic and prognostic marker for glioma.

KLF11 Expression Predicts Poor Prognosis in Glioma Patients.

PurposeGlioma is a primary intracranial malignant tumor with high recurrence and mortality rates. It is very important to study the prognostic factors. KLF11 can function as an oncogene or a tumor suppressor, depending on the tumor and tissue types and the cancer stage. In this study, we aimed to determine whether KLF11 expression is related to the overall survival of glioma patients.Patients and MethodsWe investigated KLF11 expression in 116 glioma patients with different grades using Western blot and immunohistochemistry assay. We analyzed the patients with different glioma grades and KLF11 expression levels by Kaplan–Meier survival curves. Independent prognostic factors for poor overall survival were identified by univariate and multivariate analyses.ResultsThere were 37 patients in KLF11 low expression group and 79 patients in high expression group. There was no difference in gender, age, tumor diameter or tumor location between two groups. The patients in KLF11 high expression group had higher ECOG score (P =0.025) and higher WHO grades (P =0.029). Western blot and immunohistochemistry assay showed KLF11 expression was significantly upregulated in glioma groups compared with normal brain tissues group (P < 0.05), and the expression in grades III–IV was significantly higher than those in grades I–II (P < 0.05). Kaplan–Meier survival curve analysis showed high KLF11 expression tended to reduce the overall survival (P < 0.05). After univariate and multivariate analyses, KLF11 expression (P =0.003) and age (P =0.007) were independent prognostic factors for poor survival in glioma patients.ConclusionKLF11 expression was increased in glioma tissues, and high KLF11 expression was associated with poor prognosis. KLF11 expression was an independent prognostic factor for poor survival in glioma patients. KLF11 may serve as a novel prognostic marker for gliomas and as a novel treatment target.

Glioma-Associated Stromal Cells Stimulate Glioma Malignancy by Regulating the Tumor Immune Microenvironment.

BackgroundThe glioma-associated stromal cell (GASC) is a recently identified type of cell in the glioma microenvironment and may be a prognostic marker for glioma. However, the potential mechanisms of GASCs in the glioma microenvironment remain largely unknown. In this work, we aimed to explore the mechanisms of GASCs in gliomas, particularly in high-grade gliomas (HGG).MethodsWe used glioma datasets from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). We utilized the Single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm to discriminate between patients with high or low GASC composition. The xCELL and CIBERSORT algorithms were used to analyze the composition of stromal cells and immune cells. Risk score and a nomogram model were constructed for prognostic prediction of glioma.ResultsWe observed for the first time that the levels of M2 macrophages and immune checkpoints (PD-1, PD-L1, PD-L2, TIM3, Galectin-9, CTLA-4, CD80, CD86, CD155, and CIITA) were significantly higher in the high GASC group and showed positive correlation with the GASC score in all glioma population and the HGG population. Copy number variations of DR3 and CIITA were higher in the high-GASC group. THY1, one of the GASC markers, exhibited lower methylation in the high GASC group. The constructed risk score was an independent predictor of glioma prognostics. Finally, a credible nomogram based on the risk score was established.ConclusionsGASCs stimulate glioma malignancy through the M2 macrophage, and are associated with the level of immune checkpoints in the glioma microenvironment. The methylation of THY1 could be used as prognostic indicator and treatment target for glioma. However, further studies are required to verify these findings.

TMEFF2 promoter hypermethylation is an unfavorable prognostic marker in gliomas

BackgroundTransmembrane protein with EGF-like and two follistatin-like domains 2 (TMEFF2) is a transmembrane protein in the tomoregulin family. Little research has been performed to determine whether TMEFF2 methylation is a prognostic marker in adult diffuse gliomas.MethodsIn this study, we investigated TMEFF2 expression in surgical glioma tissue samples. In addition, we conducted bisulfite amplicon sequencing (BSAS) and methylation-specific PCR (MSP) to evaluate TMEFF2 methylation in glioblastoma (GBM) cells. Subsequently, we investigated the biological function of TMEFF2 in GBM cells. Moreover, we explored the prognostic significance of TMEFF2 in gliomas by analysing a cohort dataset from TCGA.ResultsImmunohistochemistry analysis of 75 paired glioma tumour and peritumoural tissues demonstrated that glioma tumour tissues expressed lower TMEFF2 levels than peritumoural tissues (P < 0.001). TMEFF2 promoter methylation levels were increased in glioblastoma cells compared with SVG p12 cells (P < 0.001). Inhibition of methylation reduced TMEFF2 methylation and increased its expression in LN229 and T98G cells (P < 0.05). Knockdown of TMEFF2 expression significantly promoted the proliferation of U87MG cells and primary GBM cells (P < 0.05). TMEFF2 methylation is negatively associated with IDH1, ATRX and TP53 mutations, and the subtype of glioma harbouring combined IDH1/ATRX/TP53 mutations was associated with low TMEFF2 methylation levels. Survival analysis confirmed that low TMEFF2 methylation levels are associated with good prognosis in glioma patients.ConclusionsOur results suggest that TMEFF2 DNA methylation might be associated with glioma tumour progression and could serve as a valuable prognostic marker for adult diffuse gliomas.

CircRNA PIP5K1A promotes the progression of glioma through upregulation of the TCF12/PI3K/AKT pathway by sponging miR-515-5p

BackgroundIncreasing studies have revealed that circular RNAs (CircRNAs) make great contributions to regulating tumor progression. Therefore, we intended to explore the expression characteristics, function, and related mechanisms of a novel type of circRNA, PIP5K1A, in glioma.MethodsFirstly, reverse transcription-polymerase chain reaction (RT-PCR) was carried out to examine CircPIP5K1A expression in glioma tissues and adjacent normal tissues, and the correlation between CircPIP5K1A level and the clinical-pathological indicators of glioma was analyzed. Then, the CircPIP5K1A expression in various glioma cell lines was detected, and CircPIP5K1A overexpression and knockdown cell models were constructed. Subsequently, cell proliferation and viability were detected by the CCK8 method and BrdU staining. Cell apoptosis was detected by flow cytometry, and cell invasion was examined by Transwell assay. The expression of TCF12, PI3K/AKT pathway apoptotic related proteins (Caspase3, Bax, and Bcl2) and epithelial-mesenchymal transition (EMT) markers (E-cadherin, Vimentin, and N-cadherin) was determined by western blot or RT-PCR.ResultsThe results manifested that CircPIP5K1A was upregulated in glioma tissues (compared with that in normal adjacent tissues), and overexpressed CircPIP5K1A was related to glioma volume and histopathological grade. Functionally, overexpressing CircPIP5K1A notably elevated glioma cell proliferation, invasion, and EMT and inhibited apoptosis both in vivo and in vitro. Besides, CircPIP5K1A upregulated TCF12 and PI3K/AKT activation. Bioinformatics analysis testified that miR-515-5p was a common target of CircPIP5K1A and TCF12, while the dual-luciferase reporter assay and RNA immunoprecipitation (RIP) experiment further confirmed that CircPIP5K1A targeted miR-515-5p, which bound the 3′-untranslated region (UTR) of TCF12.ConclusionsOverall, the study illustrated that CircPIP5K1A is a potential prognostic marker in glioma and regulates glioma evolvement by modulating the miR-515-5p-mediated TCF12/PI3K/AKT axis.

CKAP2L Knockdown Exerts Antitumor Effects by Increasing miR-4496 in Glioblastoma Cell Lines.

Despite advances in the diagnosis and treatment of the central nervous system malignancy glioma, overall survival remains poor. Cytoskeleton-associated protein 2-like (CKAP2L), which plays key roles in neural progenitor cell division, has also been linked to poor prognosis in lung cancer. In the present study, we investigated the role of CKAP2L in glioma. From bioinformatics analyses of datasets from The Cancer Gene Atlas and the Chinese Glioma Genome Atlas, we found that CKAP2L expression correlates with tumor grade and overall survival. Gene set enrichment analysis (GSEA) showed that MITOTIC_SPINDLE, G2M_CHECKPOINT, and E2F_TARGETS are crucially enriched phenotypes associated with high CKAP2L expression. Using U87MG, U118MG, and LNZ308 human glioma cells, we confirmed that CKAP2L knockdown with siCKAP2L inhibits glioma cell proliferation, migration, invasion, and epithelial-mesenchymal transition. Interestingly, CKAP2L knockdown also induced cell cycle arrest at G2/M phase, which is consistent with the GSEA finding. Finally, we observed that CKAP2L knockdown led to significant increases in miR-4496. Treating cells with exogenous miR-4496 mimicked the effect of CKAP2L knockdown, and the effects of CKAP2L knockdown could be suppressed by miR-4496 inhibition. These findings suggest that CKAP2L is a vital regulator of miR-4496 activity and that CKAP2L is a potentially useful prognostic marker in glioma.

Identification of a three-long non-coding RNA signature for predicting survival of temozolomide-treated isocitrate dehydrogenase mutant low-grade gliomas.

Temozolomide (TMZ) is the major chemotherapy agent in glioma, and isocitrate dehydrogenase (IDH) is a well-known prognostic marker in glioma. O6-methylguanine-DNA methyltransferase promoter methylation (MGMTmethyl) is a predictive biomarker in overall gliomas rather than in IDH mutant gliomas. To discover effective biomarkers that could predict TMZ efficacy in IDH mutant low-grade gliomas (LGGs), we retrieved data of IDH mutant LGGs from TMZ arm of the EORTC22033-26033 trial as the training-set (n = 83), analyzed correlations between long non-coding RNAs (lncRNAs) and progression-free survival (PFS) using Lasso-Cox regression, and created a risk score (RS) to stratify patients. We identified a three-lncRNA signature in TMZ-treated IDH mutant LGGs. All of the three lncRNAs, as well as the RS derived, were significantly correlated with PFS. Patients were classified into high-risk and low-risk groups according to RS. PFS of the high-risk group was significantly worse than that of the low-risk group (P < 0.001). AUCs of the three-, four-, and five-year survival probability predicted by RS were 0.73, 0.79, and 0.76, respectively. The predictive role of the three-lncRNA signature was further validated in an independent testing-set, the TCGA-LGGs, which resulted in a significantly worse PFS (P < 0.001) in the high-risk group. Three-, four-, and five-year survival probabilities predicted by RS were 0.65, 0.69, and 0.84, respectively. Functions of these three lncRNAs involve cell proliferation and differentiation, predicted by their targeting cancer genes. Conclusively, we created a scoring model based on the expression of three lncRNAs, which can effectively predict the survival of IDH mutant LGGs treated with TMZ.

Identification of PIEZO1 as a potential prognostic marker in gliomas

In multiple solid tumours, including gliomas, the mechanical properties change as the disease progresses. If and how mechanical cues regulate tumour cell proliferation is currently not fully studied. PIEZO1 has recently been identified as a crucial mechanosensitive cation channel in multiple solid tumours. However, we didn’t find any clinical data describing the association between PIEZO1 expression and glioma. To investigate the role of PIEZO1 in gliomas, we analysed PIEZO1 gene expression at the transcriptome level, genomic profiles and the association of PIEZO1 with clinical practice. In total, 1633 glioma samples with transcriptome data, including data from the Chinese Glioma Genome Atlas RNAseq, the Cancer Genome Atlas RNAseq and GSE16011 databases, were included in this study. Clinical information and genomic profiles including somatic mutations were also obtained. We found that PIEZO1 expression was highly correlated with malignant clinical and molecular subtypes of glioma. Gene ontology analysis showed that expression of PIEZO1 was correlated with tumour microenvironment-related genes that encode proteins involved in extracellular matrix (ECM) organization, angiogenesis and cell migration. Additionally, PIEZO1 was shown to be involved in tumour progression by serving as the central checkpoint of multiple ECM remodelling-related signalling pathways to modulate tumour cell proliferation and the tumour microenvironment in turn. Finally, high PIEZO1 expression was correlated with reduced survival time and acted as a robust biomarker for poor prognosis in gliomas. Taken together, the results indicated that high PIEZO1 expression is closely associated with highly malignant gliomas. Importantly, PIEZO1 serves as a key factor involved in sensing mechanical properties in the tumour and can regulate both tumour cells and their microenvironment to promote glioma progression, and it is also a potential therapeutic target for the treatment of gliomas.

MiR-6869-5p Inhibits Glioma Cell Proliferation and Invasion via Targeting PGK1.

Accumulating studies have suggested the dysregulated microRNAs (miRNAs) play important roles in brain tumors, including glioma. miR-6869-5p has been documented to be aberrantly expressed in diverse cancers. However, the precise role of miR-6869-5p in glioma remains poorly understood. This study is aimed at evaluating its modifying effects on glioma. Significantly decreased expression of miR-6869-5p was found in glioma tissues and cells. Negative association was documented between miR-6869-5p and PGK1 in glioma cells, and PGK1 was demonstrated to be a targeted gene of this miRNA by luciferase reporter assay. miR-6869-5p regulated glioma cell proliferation and invasion via targeting PGK1. In addition, the survival analysis had suggested that low miR-6869-5p expression predicted poor prognosis of glioma patients. This study has suggested that miR-6869-5p is a useful tumor suppressor and prognostic marker in glioma.

Downregulation of FHL1 protein in glioma inhibits tumor growth through PI3K/AKT signaling.

Human four-and-a-half LIM domains protein 1 (FHL1) is a member of the FHL protein family, which serves an important role in multiple cellular events by interacting with transcription factors using its cysteine-rich zinc finger motifs. A previous study indicated that FHL1 was downregulated in several types of human cancer and served a role as a tumor suppressive gene. The overexpression of FHL1 inhibited tumor cell proliferation. However, to the best of our knowledge, there is no evidence to confirm whether FHL1 affected glioma growth, and the molecular mechanisms through which FHL1 represses tumor development remain unclear. In the present study, the expression level of FHL1 was determined using immunohistochemical staining in 114 tumor specimens from patients with glioma. The results indicated that FHL1 expression was negatively associated with the pathological grade of gliomas. Furthermore, Kaplan-Meier survival curves demonstrated that the patients with an increased FHL1 expression exhibited a significantly longer survival time, suggesting that FHL1 may be a prognostic marker for glioma. The protein level of FHL1 was relatively increased in the U251 glioma cell line compared with that in the U87 cell line. Therefore, FHL1 was knocked down in U251 by siRNA and overexpressed in U87, and it was identified that FHL1 significantly decreased the activation of PI3K/AKT signaling by interacting with AKT. Further experiments verified that FHL1 inhibited the growth of gliomas in vivo by modulating PI3K/AKT signaling. In conclusion, the results of the present study demonstrated that FHL1 suppressed glioma development through PI3K/AKT signaling.

Identification of Mir-9 in Glioma Diagnosis and Prognosis.

Mir-9 was recognized as a potential tumor suppressor gene or oncogene in varies of diseases; however, its roles in glioma have not been investigated. Our study was to identify the mRNA expression of mir-9 gene in glioma and correlate abnormal versions of microRNAs with clinicopathological features and investigate the impact of mir-9 in glioma prognosis. Seventy-one glioma samples, which included 22 grade II, 24 grade III, and 25 glioblastoma tumors of previously untreated patients who underwent surgical excision at Qing Hai Province People's Hospital from 2011 to 2014, were included. In addition, 2 epilepsy patients with normal brain tissue were included as a control group. The expression of mir-9 was examined by RT-PCR in formalin-fixed paraffin embedded primary tissue specimens. The clinicopathologic features, the survival rate of glioma patients were also discussed. The RNA expression of mir-9 and glioma prognosis was evaluated using a Chi-square test, Cox regression model, and GraphPad Prism survival curve analysis. There were 16, 20, 21 cases which showed high expression of mir-9 in grade II and III gliomas and glio-blastoma, 16/22 (72.7%), 20/24 (83.3%), 21/25 (84.0%), respectively. The expression of mir-9 was correlated with the grade of glioma. The mir-9 RNA expression in glioblastoma were higher than grade II and III gliomas (p < 0.05). The higher the grade, the higher the expression, and the difference was significant (p < 0.05), while it was not correlated with patient nationality, gender, or location (p > 0.05). Univariate analysis determined that high expression of mir-9, grade, chemotherapy, radiation therapy, and patient onset age were associated with glioma patient prognosis (p < 0.05). The expression of mir-9 plays a role in glioma progression, and may be used as a prognostic marker in glioma.

A novel fully automated MRI-based deep-learning method for classification of IDH mutation status in brain gliomas.

Isocitrate dehydrogenase (IDH) mutation status has emerged as an important prognostic marker in gliomas. Currently, reliable IDH mutation determination requires invasive surgical procedures. The purpose of this study was to develop a highly accurate, MRI-based, voxelwise deep-learning IDH classification network using T2-weighted (T2w) MR images and compare its performance to a multicontrast network. Multiparametric brain MRI data and corresponding genomic information were obtained for 214 subjects (94 IDH-mutated, 120 IDH wild-type) from The Cancer Imaging Archive and The Cancer Genome Atlas. Two separate networks were developed, including a T2w image-only network (T2-net) and a multicontrast (T2w, fluid attenuated inversion recovery, and T1 postcontrast) network (TS-net) to perform IDH classification and simultaneous single label tumor segmentation. The networks were trained using 3D Dense-UNets. Three-fold cross-validation was performed to generalize the networks' performance. Receiver operating characteristic analysis was also performed. Dice scores were computed to determine tumor segmentation accuracy. T2-net demonstrated a mean cross-validation accuracy of 97.14% ± 0.04 in predicting IDH mutation status, with a sensitivity of 0.97 ± 0.03, specificity of 0.98 ± 0.01, and an area under the curve (AUC) of 0.98 ± 0.01. TS-net achieved a mean cross-validation accuracy of 97.12% ± 0.09, with a sensitivity of 0.98 ± 0.02, specificity of 0.97 ± 0.001, and an AUC of 0.99 ± 0.01. The mean whole tumor segmentation Dice scores were 0.85 ± 0.009 for T2-net and 0.89 ± 0.006 for TS-net. We demonstrate high IDH classification accuracy using only T2-weighted MR images. This represents an important milestone toward clinical translation.

The Difference of Hypoxia Inducible Factor 2α mRNA Expression in High-Grade and Low-Grade Glioma Tissue

Background: HIF-2α is a transcription factor in hypoxic condition, and high expression levels of it correlate with the concepts of metastasis, therapy opposition and reduced quality of prognosis in various forms of cancerous growth. Due to the exceedingly infiltrative ability of brain glioma cells, gliomas cannot be completely deteriorated with surgery and the relapse rate is high. This study goal to identify the relative expression of HIF-2α gene in the direction of glioma malignancy and its classification. Methods: Specimens used in this research comprise of 20 glioma samples obtained from glioma patients in Cipto Mangunkusumo Hospital. Relative expression of HIF-2α was measured by utilizing quantitative Real Time-Polymerase Chain Reaction (RT-PCR). Cycle threshold (CT) values were achieved correlated with the amplified DNA, and then the relative expression was attained by using Livak method of calculation. Results: The results produced a greater average of relative expression of HIF-2α in the grade III and IV types (18.64; n=7) rather than in the lower grades (5.68; n=13). However, the data is statistically inconsequential. Conclusions: High-grade glioma tends to express HIF-2α mRNA higher compared to the lower grade. Therefore, it is possible to use HIF-2α as a prognostic marker for glioma- diagnosed patients, although additional experiments need to be performed to strengthen these facts.

Methylation and transcription patterns are distinct in IDH mutant gliomas compared to other IDH mutant cancers

Mutations in isocitrate dehydrogenases 1 and 2 (IDHmut) are present in a variety of cancers, including glioma, acute myeloid leukemia (AML), melanoma, and cholangiocarcinoma. These mutations promote hypermethylation, yet it is only a favorable prognostic marker in glioma, for reasons that are unclear. We hypothesized that the patterns of DNA methylation, and transcriptome profiles, would vary among IDHmut cancers, especially gliomas. Using Illumina 450K and RNA-Seq data from The Cancer Genome Atlas, we show that of 365,092 analyzed CpG sites, 70,591 (19%) were hypermethylated in IDHmut gliomas compared to wild-type (IDHwt) gliomas, and only 3%, 2%, and 4% of CpG sites were hypermethylated in IDHmut AML, melanoma, and cholangiocarcinoma, relative to each of their IDHwt counterparts. Transcriptome differences showed pro-malignant genes that appear to be unique to IDHmut gliomas. However, genes involved in differentiation and immune response were suppressed in all IDHmut cancers. Additionally, IDHmut caused a greater degree of hypermethylation in undifferentiated neural progenitor cells than in mature astrocytes. These data suggest that the extent and targets of IDHmut-induced genomic hypermethylation vary greatly according to the cellular context and may help explain why IDHmut is only a favorable prognostic marker in gliomas.