Prognosis Of Astrocytomas Research Articles

IGFBP7+ subpopulation and IGFBP7 risk score in astrocytoma: insights from scRNA-Seq and bulk RNA-Seq.

Glioma is the predominant malignant brain tumor that lacks effective treatment options due to its shielding by the blood-brain barrier (BBB). Astrocytes play a role in the development of glioma, yet the diverse cellular composition of astrocytoma has not been thoroughly researched. We examined the internal diversity of seven distinct astrocytoma subgroups through single-cell RNA sequencing (scRNA-seq), pinpointed crucial subgroups using CytoTRACE, monocle2 pseudotime analysis, and slingshot pseudotime analysis, employed various techniques to identify critical subgroups, and delved into cellular communication analysis. Then, we combined the clinical information of GBM patients and used bulk RNA sequencing (bulk RNA-seq) to analyze the prognostic impact of the relevant molecules on GBM patients, and we performed in vitro experiments for validation. The analysis of the current study revealed that C0 IGFBP7+ Glioma cells were a noteworthy subpopulation of astrocytoma, influencing the differentiation and progression of astrocytoma. A predictive model was developed to categorize patients into high- and low-scoring groups based on the IGFBP7 Risk Score (IGRS), with survival analysis revealing a poorer prognosis for the high-IGRS group. Analysis of immune cell infiltration, identification of genes with differential expression, various enrichment analyses, assessment of copy number variations, and evaluation of drug susceptibility were conducted, all of which highlighted their significant influence on the prognosis of astrocytoma. This research enhances comprehension of the diverse cell composition of astrocytoma, delves into the various factors impacting the prognosis of astrocytoma, and offers fresh perspectives on treating glioma.

Clinical features, MRI, molecular alternations, and prognosis of astrocytoma based on WHO 2021 classification of central nervous system tumors: A single-center retrospective study.

The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. Patients diagnosed with astrocytoma, IDH-mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2-3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki-67 index (p < 0.001) of pathological examination were statistically different in the WHO grade 2-3 group (n = 27) and WHO grade 4 group (n = 33). CDK6 (p = 0.004), FGFR2 (p = 0.003), and MYC (p = 0.004) alterations showed an enrichment in the WHO grade 4 group. Patients with higher grade showed shorter mOS (mOS = 75.9 m, 53.6 m, 26.4 m for grade 2, 3, and 4, respectively, p = 0.01). Patients diagnosed as WHO grade 4 according to the 5th edition WHO classification based on molecular alterations are more likely to have poorer prognosis. Therefore, treatment should be tailored to their individual needs. Further research is needed for the management of IDH-mutant astrocytoma is needed in the future.

CDKN2A/B Homozygous Deletions in Astrocytomas: A Literature Review.

Genomic alterations of CDKN2A and CDKN2B in astrocytomas have been an evolving area of study for decades. Most recently, there has been considerable interest in the effect of CDKN2A and/or CDKN2B (CDKN2A/B) homozygous deletions (HD) on the prognosis of isocitrate dehydrogenase (IDH)-mutant astrocytomas. This is highlighted by the adoption of CDKN2A/B HD as an essential criterion for astrocytoma and IDH-mutant central nervous system (CNS) WHO grade 4 in the fifth edition of the World Health Organisation (WHO) Classification of Central Nervous System Tumours (2021). The CDKN2A and CDKN2B genes are located on the short arm of chromosome 9. CDKN2A encodes for two proteins, p14 and p16, and CDKN2B encodes for p15. These proteins regulate cell growth and angiogenesis. Interpreting the impact of CDKN2A/B alterations on astrocytoma prognosis is complicated by recent changes in tumour classification and a lack of uniform standards for testing CDKN2A/B. While the prognostic impact of CDKN2A/B HD is established, the role of different CDKN2A/B alterations-heterozygous deletions (HeD), point mutations, and promoter methylation-is less clear. Consequently, how these alternations should be incorporated into patient management remains controversial. To this end, we reviewed the literature on different CDKN2A/B alterations in IDH-mutant astrocytomas and their impact on diagnosis and management. We also provided a historical review of the changing impact of CDKN2A/B alterations as glioma classification has evolved over time. Through this historical context, we demonstrate that CDKN2A/B HD is an important negative prognostic marker in IDH-mutant astrocytomas; however, the historical data is challenging to interpret given changes in tumour classification over time, variation in the quality of evidence, and variations in the techniques used to identify CDKN2A/B deletions. Therefore, future prospective studies using uniform classification and detection techniques are required to improve the clinical interpretation of this molecular marker.

Retracted: Identification of an m6A RNA Methylation Regulator Risk Score Model for Prediction of Clinical Prognosis in Astrocytoma

Retracted: Identification of an m6A RNA Methylation Regulator Risk Score Model for Prediction of Clinical Prognosis in Astrocytoma

Deep DNA sequencing of MGMT, TP53 and AGT in Mexican astrocytoma patients identifies an excess of genetic variants in women and a predictive biomarker.

Astrocytomas are a type of malignant brain tumor with an unfavorable clinical course. The impact of AGT and MGMT somatic variants in the prognosis of astrocytoma is unknown, and it is controversial for TP53. Moreover, there is a lack of knowledge regarding the molecular characteristics of astrocytomas in Mexican patients. We studied 48 Mexican patients, men and women, with astrocytoma (discovery cohort). We performed DNA deep sequencing in tumorsamples, targeting AGT, MGMT and TP53, and we studied MGMT gene promoter methylation status. Then we compared our findings to a cohort which included data from patients with astrocytoma from The Cancer Genome Atlas (validation cohort). In the discovery cohort, we found a higher number of somatic variants in AGT and MGMT than in the validation cohort (10.4% vs < 1%, p < 0.001), and, in both cohorts, we observed only women carried variants AGT variants. We also found that the presence of either MGMT variant or promoter methylation was associated to better survival and response to chemotherapy, and, in conjunction with TP53 variants, to progression-free survival. The occurrence of AGT variants only in women expands our knowledge about the molecular differences in astrocytoma between men and women. The increased prevalence of AGT and MGMT variants in the discovery cohort also points towards possible distinctions in the molecular landscape of astrocytoma among populations. Our findings warrant further study.

Alpha2beta1 Integrin Polymorphism in Diffuse Astrocytoma Patients.

Integrins are heterodimeric transmembrane glycoproteins resulting from the non-covalent association of an α and β chain. The major integrin receptor for collagen/laminin, α2β1 is expressed on a wide variety of cell types and plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Integrin-triggered signaling pathways promote the invasion and survival of glioma cells by modifying the brain microenvironment. In this study, we investigated the association of a specific genetic polymorphism of integrin α2β1 with the incidence of diffusely infiltrating astrocytoma and the progression of these tumors. Single-nucleotide polymorphism in intron 7 of the integrin ITGA2 gene was examined in 158 patients and 162 controls using polymerase chain reaction and restriction enzyme analysis. The ITGA2 genotype +/+ (with a BglII restriction site in both alleles) exhibited higher frequency in grade II astrocytoma compared to control (P = 0.02) whereas the genotype -/- (lacking the BglII site) correlated with the poorest survival rate (P = 0.04). In addition, in silico analyses of ITGA2 expression from low-grade gliomas (LGG, n = 515) and glioblastomas (GBM, n = 159) indicated that the higher expression of ITGA2 in LGG was associated with poor overall survival (P < 0.0001). However, the distribution of integrin ITGA2 BglII genotypes (+/+, +/-, -/-) was not significantly different between astrocytoma subgroups III and IV (P = 0.65, 0.24 and 0.33; 0.29, 0.48, 0.25, respectively) compared to control. These results suggest a narrow association between the presence of this SNP and indicate that further studies with larger samples are warranted to analyze the relation between tumor grade and overall survival, highlighting the importance of determining these polymorphisms for prognosis of astrocytomas.

Identification of an m6A RNA Methylation Regulator Risk Score Model for Prediction of Clinical Prognosis in Astrocytoma.

Astrocytoma (AS) is the most ubiquitous primary malignancy of the central nervous system (CNS). The vital involvement of the N6-methyladenosine (m6A) RNA modification in the growth of multiple human tumors is known. This study entailed probing m6A regulators with AS prognosis to construct a risk prediction model (RS) for potential clinical use. A total of 579 AS patients' (of the Chinese Glioma Genome Atlas,CGGA) data and the expression of 12 published m6A-related genes were included in this study. Cox and selection operator (LASSO) regression analyses for independent prognostic factors and multifactor Cox analysis established an R.S. model to predict the AS patient prognosis. This was subject to verification employing 331 samples from the TCGA data set followed by gene ontology and pathway enrichment study with gene set enrichment analysis (GSEA). The R.S. constructed with three m6A genes inclusive of WTAP, RBM15, and YTHDF2 emerged as independent prognostic factors in AS patients with vital involvement in the advancement and development of the malignancy. In a nutshell, this work reported an m6A-related gene risk model to predict the prognosis of AS patients to pave the way for discerning diagnostic and prognostic biomarkers. Further corroboration employing relevant wet-lab assays of this model is warranted.

Chaperonin-containing tailless complex polypeptide 1 subunit 6A correlates with increased World Health Organization grade, less isocitrate dehydrogenase mutation, and deteriorative survival of astrocytoma patients.

ObjectiveChaperonin‐containing tailless complex polypeptide 1 subunit 6A (CCT6A) is reported to be an efficient prognostic biomarker in various cancers, but it is rarely reported in astrocytoma. Thus, this study aimed to evaluate the expression of CCT6A and its correlation with disease features and prognosis in astrocytoma patients.MethodsTotally, 198 astrocytoma patients who received surgery treatment were enrolled. CCT6A protein expression was determined in the tumor tissues fixed in formalin and embedded in paraffin (FFEP) by immunohistochemistry (IHC) assay. In addition, 133 out of 198 astrocytoma patients had fresh tumor tissues frozen in the liquid nitrogen for the determination of CCT6A mRNA expression by reverse transcription‐quantitative polymerase chain reaction.ResultsSixty‐nine (34.8%), 70 (35.4%), 46 (23.2%), and 13 (6.6%) astrocytoma patients had the CCT6A immunohistochemistry (IHC) score of 0–3, 4–6, 7–9, and 10–12, respectively. CCT6A protein expression was correlated with increased World Health Organization (WHO) grade (P < 0.001) and less isocitrate dehydrogenase (IDH) mutation (P = 0.002); meanwhile, CCT6A mRNA expression was only related to elevated WHO grade (P = 0.001). However, CCT6A protein and mRNA expression were not correlated with other clinical features and subsequent treatment modalities (all P > 0.05). Moreover, CCT6A protein high and CCT6A mRNA high were related to shorter accumulating overall survival (OS; both P < 0.05). CCT6A protein high was an independent factor for predicting the worse OS (hazard ratio: 1.821, P = 0.012).ConclusionChaperonin‐containing tailless complex polypeptide 1 subunit 6A correlates with elevated WHO grade and less IDH mutation; besides, CCT6A high expression is independently associated with unfavorable accumulating OS of astrocytoma patients.

Integrated genomic and transcriptomic analysis identified KRT18 mutation and MTAP loss as key genetic alterations related to the prognosis of astrocytoma and glioblastoma.

e14039 Background: Astrocytoma and glioblastoma (GBM) are two main subtypes of glioma classified by WHO guide of center nervous system (CNS) tumors to different grades. GBM is the most malignant among all CNS tumors with a 5-year survival rate of less than 5%. Although the prognosis of patients with astrocytoma is better than that of GBM in general, astrocytoma patients with IDH wild-type have a similar prognosis as GBM. Exploring the molecular driving force behind the malignant phenotype of astrocytoma and GBM will help explain the diversity of glioma and discover new drug targets. Methods: We enrolled 12 patients with astrocytoma and 12 patients with GBM and performed whole-exome sequencing (WES) and RNA-seq analysis on tumor samples from the patients. Comparative analysis of somatic mutation, copy number variation, cytoband alteration and differently expressed genes were performed between astrocytoma and GBM. Immune cells infiltration was analyzed by CIBERSORT Algorithm with LM22 immune subsets. Results: This study includes 14 male patients and 10 female patients, and the median age was 45.5 (range, 18-68) years old. Seven patients had IDH1 mutation, including 6 patients with astrocytoma and 1 patient with GBM. Somatic mutation of KRT18, which is associated with cell apoptosis and adhesion by interacting with TRADD and Pinin , was significantly enriched in astrocytoma, but rare in GBM. Copy number loss of MTAP, which is a potential drug target and closely related to a poor prognosis of glioma, was found significantly enriched in GBM. Pathway enrichment analysis found that GBM was mainly enriched in tumor-related pathways, such as cell adhesion, cell division, and angiogenesis, but astrocytoma was mainly enriched in pathways with ion transport, cell-cell signaling and neurogenesis. Immune cells infiltration analysis showed that macrophages M0 was significantly enriched in GBM, and activated mast cells, monocytes and plasma cells were significantly enriched in astrocytoma. Conclusions: This study revealed the distinct characteristics of astrocytoma and GBM at the DNA and RNA levels. Somatic mutation of KRT18, which was first reported in glioma, may be closely related to the malignant phenotype of astrocytoma. Copy number loss of MTAP, which was associated with the susceptibility to purine starvation and specific chemotherapy, was a key genetic alterative gene in GBM and had the potential to become the therapeutic target of GBM.

Chromatin-regulating genes are associated with postoperative prognosis and isocitrate dehydrogenase mutation in astrocytoma.

BackgroundAbnormality in chromatin regulation is a major determinant in the progression of multiple neoplasms. Astrocytoma is a malignant histologic morphology of glioma that is commonly accompanied by chromatin dysregulation. However, the systemic interpretation of the expression characteristics of chromatin-regulating genes in astrocytoma is unclear.MethodsIn this study, we investigated the expression profile of chromatin regulation genes in 194 astrocytoma patients sourced from The Cancer Genome Atlas (TCGA) database. The relevance of gene expression and postoperative survival outcomes was assessed.ResultsBased on the expression patterns of chromatin regulation genes, two primary clusters and three subclusters with significantly different survival outcomes were identified. The patients in cluster_1 (or subcluster_1) had a poorer prognosis than the other groups, and this particular cohort were older, with a more advanced grade of tumor and isocitrate dehydrogenase-wildtype distribution. Detection of the differentially expressed genes revealed that the group with poor prognosis was characterized by downregulation of H2AFY2, WAC, HDAC5, ZMYND11, TET1, SATB1, and MYST4, and overexpression of EYA4. Moreover, all eight genes were significantly correlated with overall survival (OS) in astrocytoma. Age-associated genes were investigated and the expression levels of EYA4, TET1, SATB1, WAC, ZMYND11, and H2AFY2 were found to be closely correlated with advanced age. Regression analysis suggested that the expression levels of H2AFY2, HILS1, EYA1, EYA4, and KDM5B were independently associated with IDH mutation status. The differential expressions of 34 common genes were significantly associated with age, grade, and IDH mutant.ConclusionsThe study revealed that the expression pattern of chromatin regulation genes was significantly associated with postoperative prognosis in astrocytoma. Moreover, the differential expression of particular genes was strongly associated with clinical characteristics such as age, grade, and IDH subtype. These results suggest that the genes involved in chromatin regulation play important roles in the biological process of astrocytoma progression, and these molecules could potentially serve as therapeutic targets in astrocytoma.

Identification of tumor microenvironment-related genes in lower-grade gliomas by mining TCGA database.

BackgroundLower-grade gliomas (LGGs) are ubiquitous and fatal branches of brain neoplasm. Finding biomarkers related to diagnosis and treatment is essential for the treatment of LGG. It is possible to reveal the potential links between tumor microenvironment and overall survival (OS) in LGG by mining the mRNA expression profile from the TCGA database. Our primary purpose was to explore key genes that can be applied for diagnosis or treatment in LGG microenvironment.MethodsBased on the ESTIMATE algorithm, the immune and stromal scores were calculated to measure the extent of infiltration of immune cells and stromal cells, respectively. The LGG samples from TCGA database were assigned into high- or low-score groups per the immune and stromal scores and differentially expressed genes (DEGs) were selected by comparing gene expression levels in the two groups. Functional enrichment analysis and protein-protein interaction (PPI) networks were performed to analyze DEGs. Finally, selected DEGs were validated using another independent LGG cohort from CGGA dataset.ResultsThe results indicated that immune/stromal scores correlated with LGG prognosis. Furtherly, survival analysis conducted for each subtype shown that immune/stromal scores were only significantly associated with the prognosis of astrocytoma, IDH-wildtype, and there was no significant statistical difference in the other subtypes. Functional enrichment analysis and protein-protein interaction (PPI) networks further showed that the upregulated DEGs were primarily involved in immune response, plasma membrane, and cytokine binding. Accordingly, a series of genes that have significant impacts on prognosis and are significantly associated with the tumor microenvironment were obtained.ConclusionsBased on the ESTIMATE algorithm, we first explored the relationship between immune/stromal scores and prognosis in different subtypes of LGG and the result shown that the scores were only strongly associated with the prognosis of astrocytoma, IDH-wildtype. Furtherly, a comprehensive bioinformatics analysis of the gene expression profiles of astrocytoma, IDH-wildtype patients was conducted, CASP8, TRIM6, TRIM38, PARP9, NMI, EPSTI1, DTX3L and AGBL2 were identified as tumor microenvironment-related genes, may be involved in the occurrence, development, and invasion of LGG.

Abstract C129: MicroRNA-155 targets AGTR1/NF-κB /CXCR4 axis and attenuates oncogenesis in glioblastoma

Abstract Glioblastoma (GBM) is the most aggressive malignancy of all primary brain tumors. Despite the recent advances in GBM treatment, the average survival time for a patient is less than 15 months. Therefore, we sought to investigate the molecular mechanisms underlying GBM initiation, progression and identify novel drug targets for this deadly disease. Higher levels of Angiotensin II Receptor Type 1 (AGTR1) and Angiotensin II Receptor Type 2 (AGTR2) have been associated with poor patient prognosis in astrocytomas. Additionally, contribution of these receptors in proliferative and infiltrative properties of glioma cells has already been established. Moreover, overexpression of AGTR1 has been known to play a critical role in multiple human malignancies including brain. However, the underlying mechanism involved in AGTR1 upregulation in GBM is not clearly understood and remains a matter of conjecture. Here, we analysed online available RNA-seq data from two independent GBM patients’ cohorts for AGTR1 expression and observed significant overexpression of AGTR1 in glioma patients compared to normal adjacent tissue. Importantly, the overall survival probability of GBM patients with high AGTR1 expression was low as compared to patients with low AGTR1 levels. To understand the post-transcriptional regulation of AGTR1 in GBM, we employed miRNA prediction algorithms namely, TargetScan, miRanda (microRNA.org), MicroT4 (DIANA tools), RNA22 along with experimentally supported database (TarBase), and examined miRNAs that bind to 3’UTR of AGTR1. Interestingly, conserved binding of miRNA-155 was predicted by all algorithms. Further, AGTR1-3’UTR-luciferase reporter assay in HEK-293T cells also confirmed the miRNA-155 mediated post-transcriptional regulation of AGTR1. Moreover, ectopic expression of miRNA-155 in GBM cells abrogate AGTR1-mediated proliferation, invasion, foci formation and anchorage independent growth. Intriguingly, immunodeficient mice implanted with stable miRNA-155 overexpressing SNB19 cells showed a significant reduction (~95%) in tumor burden as compared to the control group. Mechanistically, we showed that miRNA-155 attenuates AGTR1-mediated epithelial-to-mesenchymal transition, angiogenesis, ERK/MAPK signaling and promotes apoptosis. Importantly, stimulation with Angiotensin II (Ang II), a bonafide ligand of AGTR1, results in activation of NF-κB signaling downstream of AGTR1, followed by an increase in expression of C-X-C chemokine receptor type 4 (CXCR4) and AGTR1. Conversely, miRNA-155 overexpression in GBM cells attenuate NF-κB signalling, leading to a notable decrease in the expression of CXCR4 and its downstream signalling accompanied with reduction in AGTR1 levels. Alternately, we treated GBM cells with IKK-16, an inhibitor of IKK complex, to abrogate the NF-κB signalling downstream of AGTR1. Interestingly, we observed a significant reduction in the AGTR1 expression along with a marked decrease in CXCR4 expression. Taken together, we demonstrate that miRNA-155 is involved in post-transcriptional regulation of AGTR1 and disrupts AGTR1/NF-κB /CXCR4 signaling axis via anticancer pleiotropic effects. The present study opens new avenues to use IKK inhibitors and possible use of miRNA-155 replacement therapy for AGTR1-positive malignancies. Citation Format: Anukriti Singh, Nidhi Srivastava, Bushra Ateeq. MicroRNA-155 targets AGTR1/NF-κB /CXCR4 axis and attenuates oncogenesis in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C129. doi:10.1158/1535-7163.TARG-19-C129

Impact of AKAP6 polymorphisms on Glioma susceptibility and prognosis

PurposeGlioma is the most common primary malignant brain tumor with high mortality and poor prognosis. Our aim was to clarify the correlation between Kinase-anchored protein 6 (AKAP6) gene polymorphisms and glioma susceptibility and prognosis in Chinese Han population.MethodsFive single-nucleotide polymorphisms (SNPs) of AKAP6 were genotyped by Agena MassARRAY in 575 glioma patients and 500 healthy controls. Logistic regression model was utilized to calculate odds ratios (OR) and 95% confidence intervals (CI). The associations between polymorphisms and survival were assessed using the log-rank test, Kaplan-Meier analysis and Cox regression model.ResultsWe found that rs2239647 polymorphism was strongly associated with an increased risk of glioma (OR = 1.90, p = 0.007) and a worse prognosis for glioma, especially in high-grade glioma (HR = 1.67, p = 0.034). Stratified analysis showed that rs2239647 increased the risk of glioma in female (OR = 1.62, p = 0.016). Whereas, rs4261436 (HR = 0.70, p = 0.045) and rs17522122 (HR = 0.75, p = 0.016) were associated with better prognosis of astrocytoma. In addition, we also found that surgical methods and chemotherapy are critical factors for the prognosis of glioma patients.ConclusionsThis study firstly provided evidence for the impact of AKAP6 polymorphisms on susceptibility and prognosis of glioma, suggesting AKAP6 variants might have potential roles in the etiology of glioma.

LPP and RYR2 Gene Polymorphisms Correlate with the Risk and the Prognosis of Astrocytoma.

Astrocytoma is the most common neuroepithelial tumor. Genetic factors play an important role in the development and prognosis of astrocytoma. So this study focuses on the impact of LPP and RYR2 genes on the occurrence and prognosis of astrocytoma. Rs12594 and rs16835904 in the RYR2 gene and rs1064607, rs3796283, and rs2378456 in the LPP gene were selected and genotyped using Agena MassARRAY in 365 patients and 379 healthy populations. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined using logistic regression to assess the influence of gene polymorphisms on occurrence of astrocytoma. The association between genotype and survival outcomes was performed by the Kaplan-Meier method, the log-rank test, and the Cox regression analysis. The survival rates of patients receiving gross total resection and postoperative chemotherapy were higher than patients receiving near total resection and subtotal resection and without chemotherapy. In recessive model, the patients with LPP rs2378456 CC genotype increased the risk of astrocytoma (OR = 1.43, 95% CI 1.01-2.02, p = 0.042). Stratified analysis shows that RYR2 rs16835904 TC-TT genotype facilitated the risk of astrocytoma in male (OR = 1.93, 95% CI 1.15-3.24, p = 0.011). Cox regression analysis shows that RYR2 rs12594 AA genotype and AG genotype were associated with OS of astrocytoma (AG genotype: HR = 1.62, 95% CI 1.04-2.53, p = 0.034; AA genotype: HR = 1.70, 95% CI 1.08-2.68, p = 0.021). RYR2 and LPP genes were found to affect the occurrence and prognosis of astrocytoma.

Total copy number variation as a prognostic factor in adult astrocytoma subtypes

Since the discovery that IDH1/2 mutations confer a significantly better prognosis in astrocytomas, much work has been done to identify other molecular signatures to help further stratify lower-grade astrocytomas and glioblastomas, with the goal of accurately predicting clinical outcome and identifying potentially targetable mutations. In the present study, we subclassify 135 astrocytomas (67 IDH-wildtype and 68 IDH-mutant) from The Cancer Genome Atlas dataset (TCGA) on the basis of grade, IDH-status, and the previously established prognostic factors, CDK4 amplification and CDKN2A/B deletion, within the IDH-mutant groups. We analyzed these groups for total copy number variation (CNV), total mutation burden, chromothripsis, specific mutations, and amplifications/deletions of specific genes/chromosomal regions. Herein, we demonstrate that across all of these tumor groups, total CNV level is a relatively consistent prognostic factor. We also identified a trend towards increased levels of chromothripsis in tumors with lower progression-free survival (PFS) and overall survival (OS) intervals. While no significant differences were identified in overall mutation load, we did identify a significantly higher number of cases with mutations in genes with functions related to maintaining genomic stability in groups with higher mean CNV and worse PFS and OS intervals, particularly in the IDH-mutant groups. Our data further support the case for total CNV level as a potential prognostic factor in astrocytomas, and suggest mutations in genes responsible for overall genomic instability as a possible underlying mechanism for some astrocytomas with poor clinical outcome.

Angiotensinogen rs5050 germline genetic variant as potential biomarker of poor prognosis in astrocytoma.

IntroductionRenin-angiotensin system (RAS) in brain cancer represents a scarcely explored field in neuro-oncology. Recently, some pre- and clinical studies have reported that RAS components play a relevant role in the development and behavior of gliomas. The angiotensinogen (AGT) rs5050 genetic variant has been identified as a crucial regulator of the transcription of AGT mRNA, which makes it a logical and promising target of research. The aim of this study was to determine the relationship between the AGT rs5050 genetic variant in blood with prognosis in astrocytoma.MethodsA prospective pilot study was performed on forty-eight astrocytoma patients, who received the standard-of-care treatment. Blood samples were taken prior to surgery and DNA was sequenced using Ion Torrent next-generation sequencing and analyzed by Ion Reporter software. Descriptive, bivariate, multivariate, and survival analyses were performed using SPSS v21, STATA 12 and GraphPad Prism 7.ResultsMedian follow-up was 41 months (range 1–48). Survival analysis showed a significant difference between the rs5050 genotypes (p = .05). We found lower survival rates in individuals with the GG-genotype of rs5050 AGT compared to patients with the TT- and TG-genotype (2 months vs. 11.5 months, respectively [p = .01]). In bivariate and multivariate analyses, GG-genotype was negatively associated with survival.ConclusionsIn patients with astrocytoma, AGT rs5050 GG-genotype was associated with poor prognosis. We propose this germline genetic variant as a complementary biomarker, which can be detected practically and safely in blood samples or saliva.

High-level Sp1 is Associated with Proliferation, Invasion, and Poor Prognosis in Astrocytoma.

Astrocytoma is the most common and the most lethal primary brain tumor in adults. Grade IV glioblastoma is usually refractory to currently available surgical, chemotherapeutic, and radiotherapeutic treatments. The Specificity protein 1 (Sp1) transcription factor is known to regulate tumorigenesis in many cancers. The aim of this study was to investigate the clinicopathologic role of Sp1 protein in the carcinogenesis of astrocytoma. This study analyzed 98 astrocytoma cases treated at Kaohsiung Medical University Hospital during 2002-2012. Clinicopathologic parameters associated with Sp1 were analyzed by chi-square test, Kaplan-Meier analysis, and Cox regression analyses. In vitro proliferation, invasion, and migration were compared between non-siRNA groups and Sp1 siRNA groups. In glioblastoma cells treated with Sp1 siRNA, Western blot was also used to detect expressions of Sp1, Ki-67, VEGF, cyclin D1, E-cadherin, cleaved caspase-3 and Bax proteins. Expression of Sp1 was significantly associated with WHO grade (p = 0.005) and with overall survival time (p < 0.001). Multivariate analysis further revealed that prognosis of astrocytoma was significantly associated with Sp1 expression (p = 0.036) and IDH-1 expression (p < 0.001). In vitro silencing of Sp1 downregulated Sp1, Ki-67, and cyclin D1 but upregulated E-cadherin, Bax, and cleaved caspase-3. These data suggest that Sp1 is a potential prognostic marker and therapeutic target in astrocytoma.

Elevated expression of HSP10 protein inhibits apoptosis and associates with poor prognosis of astrocytoma.

Astrocytoma is the most common type of primary malignant brain tumor, with pretty lowly 5-year survival rate in patients. Although extended surgical removal of the tumor and postoperative chemotherapy/radiotherapy executed, still there is large recurrence rate, mainly because diffuse glioma tumor cells ubiquitously infiltrate into normal parenchyma. So it becomes a priority to hunt novel molecular and signaling pathway targets to suppress astrocyma progression. HSP10, an important member of Heat shock proteins (Hsps) family, classically works as molecular chaperone folding or degradating of target proteins. Evolutionarily, HSP10 is also reported to be involved in immunomodulation and tumor progression. Poly (ADP-ribose) polymerase (PARP), important in DNA repair, is one of the main cleavage targets of caspase. And cleaved PARP (c-PARP) can serve as a marker of cells undergoing apoptosis. So far, whether the expression of HSP10 or c-PARP is associated with clinicopathologic implication for astrocytoma has not been reported. Meanwhile, it is unclear about the relationship between HSP10 and cell apoptosis. The purpose of this research is to elucidate the association between the expression of HSP10 and c-PARP and clinicopathological characteristics of astrocytoma by immunohistochemistry. The results showed that positive percentage of high HSP10 expression in astrocytoma 42/103, 40.8%) was significantly higher than that in the non-tumor control brain tissues (8/43, 18.6%) (P = 0.01). While no apparent difference of high c-PARP expression existed between astrocytoma and non-tumor control brain tissues. Furthermore, elevated expression of HSP10 was negative related to low expression of c-PARP (r = -0.224, P = 0.023), indicating high expression of HSP10 in astrocytoma inhibited apoptosis process effectively. And overexpression of HSP10 was proved to be the independent poor prognostic factor for astrocytoma by multivariate analysis. Taken together, our results suggest that elevated expression of HSP10 protein inhibits apoptosis and associates with poor prognosis of astrocytoma.

Combination of AQP1 and β-catenin expression is an independent prognosis factor in astrocytoma patients.

Previous research usually focused on single protein or gene in tumor development, actually highly heterogeneous nature and different signaling pathways largely contribute to tumor progression and tumor patients’ outcomes. Therefore, using combinatorial biomarkers to evaluate the prognostic features and guide management is gradually accepted and urgently needed. β-catenin is a well-known crucial factor in astrocytoma progression and it is involved in aquaporin1 (AQP1) mediated cell migration. In this study, we revealed the function of AQP1 in astrocytoma progression and provided the first clinical evidence that AQP1 expression was positively correlated with β-catenin. Furthermore, we proved the functional role of AQP1/β-catenin pathway in astrocytoma progression. More importantly, we discovered that combination of AQP1 and β-catenin expression was an independent prognosis factor for astrocytoma patients and it was a better survival predictor than either AQP1 or β-catenin alone. In conclusion, our study provided a novel more precise prognostication for predicting astrocytoma prognosis based on combinatorial analysis of AQP1 and β-catenin expression.

PROGNOSTIC VALUE OF COMBINED IMMUNOHISTOCHEMICAL EXPRESSION OF BMI1 AND EZH2 IN ASTROCYTOMA

Background: Although current improvements in surgery, chemotherapy and radiotherapy, the still survival of astrocytoma’s patient is poor. It is assumed that the combined expression of BMI1 and EZH2 may be associated with malignant transformation of astrocytomas and also it may reveal the biological aggressiveness of this disease. Aim of work: assessment the value of the combined immunohistochemical expression of BMI1 and EZH2 and their correlation with the clinicopathological characters and prognosis in astrocytoma patient. Subjects & Methods: BMI1 and EZH2 expressions were evaluated using immunohistochemical staining in 70 patients 40 cases with astrocytomas and 30 cases of non-neoplastic brain tissue. The relationship between their expressions and clinicopathological factors were analyzed. Results: A significant difference (P 0.05). The spearman correlation analysis revealed a significant positive association betweenBMI1 and EZH2 expressions (r = 0.311; P=0.05) revealing direct relationship betweenBMI1 and EZH2. Conclusions: BMI1 and EZH2 were involved in astrocytoma malignant transformation and poor prognosis in astrocytoma particularly glioblastoma. Keywords: BMI1, EZH2, astrocytoma, PcG, glioblastoma and GSCs.