Jiangfei Wang

A three-gene signature for prognosis in patients with MGMT promoter-methylated glioblastoma

Glioblastoma is the most malignant tumor and has high mortality rate. The methylated prompter of MGMT results in chemotherapy sensitivity for these patients. However, there are still other factors that affected the prognosis for the glioblastoma patients with similar MGMT methylation status. We developed a signature with three genes screened from the whole genome mRNA expression profile from Chinese Glioma Genome Atlas (CGGA) and RNAseq data from The Cancer Genome Atlas (TCGA). Patients with MGMT methylation in low risk group had longer survival than those in high risk group (median overall survival 1074 vs. 372 days; P = 0.0033). Moreover, the prognostic value of the signature was significant difference in cohorts stratified by MGMT methylation and chemotherapy (P=0.0473), while there is no significant difference between low and high risk group or unmethylated MGMT patients without chemotherapy. Multivariate analysis indicated that the risk score was an independent prognosis factor (P = 0.004). In conclusion, our results showed that the signature has prognostic value for patients with MGMT promoter-methylated glioblastomas based on bioinformatics analysis.

LncRNA profile study reveals four-lncRNA signature associated with the prognosis of patients with anaplastic gliomas

Anaplastic glioma is Grade III and the median overall survival is about 37.6 months. However, there are still other factors that affect the prognosis for anaplastic glioma patients due to variable overall survival. So we screened four-lncRNA signature (AGAP2-AS1, TPT1-AS1, LINC01198 and MIR155HG) from the lncRNA expression profile from the GSE16011, CGGA and REMBRANDT datasets. The patients in low risk group had longer overall survival than high risk group (median OS 2208.25 vs. 591.30 days; P < 0.0001). Moreover, patients in the low risk group showed similar overall survival to Grade II patients (P = 0.1669), while the high risk group showed significant different to Grade IV (P = 0.0005) with similar trend. So based on the four-lncRNA, the anaplastic gliomas could be divided into grade II-like and grade IV-like groups. On the multivariate analysis, it showed the signature was an independent prognostic factor (P = 0.000). The expression of four lncRNAs in different grades showed that AGAP2-AS1, LINC01198 and MIR155HG were increased with tumor grade, while TPT1-AS1 was decreased. Knockdown of AGAP2-AS1 can inhibit the cell proliferation, migration and invasion, while increase the apoptosis cell rates in vitro. In conclusion, our results showed that the four-lncRNA signature has prognostic value for anaplastic glioma. Moreover, clinicians should conduct corresponding therapies to achieve best treatment with less side effects for two groups patients.

Integrated Analysis of LncRNA-mRNA Co-Expression Profiles in Patients with Moyamoya Disease

Moyamoya disease (MMD) is an idiopathic disease associated with recurrent stroke. However, the pathogenesis of MMD remains unknown. Therefore, we performed long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in blood samples from MMD patients (Nu2009=u200915) and healthy controls (Nu2009=u200910). A total of 880 differentially expressed lncRNAs (3649 probes) and 2624 differentially expressed mRNAs (2880 probes) were obtained from the microarrays of MMD patients and healthy controls (Pu2009<u20090.05; Fold Change >2.0). Gene ontology (GO) and pathway analyses showed that upregulated mRNAs were enriched for inflammatory response, Toll-like receptor signaling pathway, chemokine signaling pathway and mitogen-activated protein kinase (MAPK) signaling pathway among others, while the downregulated mRNAs were enriched for neurological system process, digestion, drug metabolism, retinol metabolism and others. Our results showed that the integrated analysis of lncRNA-mRNA co-expression networks were linked to inflammatory response, Toll-like signaling pathway, cytokine-cytokine receptor interaction and MAPK signaling pathway. These findings may elucidate the pathogenesis of MMD, and the differentially expressed genes could provide clues to find key components in the MMD pathway.

Identification of a Long Noncoding RNA-Associated Competing Endogenous RNA Network in Intracranial Aneurysm.

BACKGROUNDnIntracranial aneurysm (IA) is a cerebrovascular disorder characterized by an abnormally bulged artery in the brain and subarachnoid hemorrhage caused by IA rupture with a high ratio of fatality and morbidity. However, the genetic cause of IA remains largely unknown.nnnMETHODSnA dysregulated long noncoding RNA (lncRNA) -associated competing endogenous RNA (ceRNA) network was constructed by using sample-matched microRNA (miRNA), lncRNA, and messenger (mRNA) expression profiles in 12 saccular IA samples and paired control arteries.nnnRESULTSnIn this study, 1150 lncRNAs, 2545 mRNAs, and 286 miRNAs were differentially expressed in IAs compared with control arteries. Using miRanda, a ceRNA score was assigned, and gene expression methods were used to construct a ceRNA network. The network consists of 8401 miRNA-lncRNA-mRNA interactions (199 miRNAs, 445 lncRNAs, 1116 mRNAs; P < 0.05). Further Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the mRNAs involved in the ceRNA network were involved in the regulation of muscle contraction and vascular smooth muscle contraction.nnnCONCLUSIONSnBy comparing IAs and their control arteries, we identified differentially expressed lncRNAs, miRNAs, and mRNAs and suggested ceRNA roles in the pathogenesis of IA. These findings may help to characterize the pathogenesis of IA and provide novel therapeutic targets in the future for patients with IA.

Aberrant expression of lncRNAs and mRNAs in patients with intracranial aneurysm

Intracranial aneurysm (IA) is pathological dilatations of the cerebral artery and rupture of IAs can cause subarachnoid hemorrhage, which has a high ratio of fatality and morbidity. However, the pathogenesis of IAs remains unknown. We performed long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in IA tissues and superficial temporal arteries (STAs). A total of 4129 differentially expressed lncRNAs and 2926 differentially expressed mRNAs were obtained from the microarrays (P < 0.05). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that up-regulated mRNAs were enriched in immune response, inflammatory response, regulation of immune response and lysosome, et al; while the down-regulated mRNAs were enriched in muscle contraction, smooth muscle contraction, cGMP-PKG signaling pathway and vascular smooth muscle contraction, et al. The lncRNA-mRNA co-expression networks were represented in immune response, inflammatory response, muscle contraction and vascular smooth muscle contraction. These findings may gain insight in the pathogenesis of IAs and provide clues to find key roles for IA patients.

An immune-related lncRNA signature for patients with anaplastic gliomas

We investigated immune-related long non-coding RNAs (lncRNAs) that may be exploited as potential therapeutic targets in anaplastic gliomas. We obtained 572 lncRNAs and 317 immune genes from the Chinese Glioma Genome Atlas microarray and constructed immune-related lncRNAs co-expression networks to identify immune-related lncRNAs. Two additional datasets (GSE16011, REMBRANDT) were used for validation. Gene set enrichment analysis and principal component analysis were used for functional annotation. Immune-lncRNAs co-expression networks were constructed. Nine immune-related lncRNAs (SNHG8, PGM5-AS1, ST20-AS1, LINC00937, AGAP2-AS1, MIR155HG, TUG1, MAPKAPK5-AS1, and HCG18) signature was identified in patients with anaplastic gliomas. Patients in the low-risk group showed longer overall survival (OS) and progression-free survival than those in the high-risk group (Pu2009<u20090.0001; Pu2009<u20090.0001). Additionally, patients in the high-risk group displayed no-deletion of chromosomal arms 1p and/or 19q, isocitrate dehydrogenase wild-type, classical and mesenchymal TCGA subtype, G3 CGGA subtype, and lower Karnofsky performance score (KPS). Moreover, the signature was an independent factor and was significantly associated with the OS (Pu2009=u20090.000, hazard ratio (HR)u2009=u20091.434). These findings were further validated in two additional datasets (GSE16011, REMBRANDT). Low-risk and high-risk groups displayed different immune status based on principal components analysis. Our results showed that the nine immune-related lncRNAs signature has prognostic value for anaplastic gliomas.

The pathogenesis shared between abdominal aortic aneurysms and intracranial aneurysms: a microarray analysis

Abdominal aortic aneurysms (AAAs) and intracranial saccular aneurysms (IAs) are the most common types of aneurysms. This study was to investigate the common pathogenesis shared between these two kinds of aneurysms. We collected 12 IAs samples and 12 control arteries from the Beijing Tiantan Hospital and performed microarray analysis. In addition, we utilized the microarray datasets of IAs and AAAs from the Gene Expression Omnibus (GEO), in combination with our microarray results, to generate messenger RNA expression profiles for both AAAs and IAs in our study. Functional exploration and protein–protein interaction (PPI) analysis were performed. A total of 727 common genes were differentially expressed (404 was upregulated; 323 was downregulated) for both AAAs and IAs. The GO and pathway analyses showed that the common dysregulated genes were mainly enriched in vascular smooth muscle contraction, muscle contraction, immune response, defense response, cell activation, IL-6 signaling and chemokine signaling pathways, etc. The further protein–protein analysis identified 35 hub nodes, including TNF, IL6, MAPK13, and CCL5. These hub node genes were enriched in inflammatory response, positive regulation of IL-6 production, chemokine signaling pathway, and T/B cell receptor signaling pathway. Our study will gain new insight into the molecular mechanisms for the pathogenesis of both types of aneurysms and provide new therapeutic targets for the patients harboring AAAs and IAs.

Regional specificity of 1p/19q co-deletion combined with radiological features for predicting the survival outcomes of anaplastic oligodendroglial tumor patients

In this study we aimed to identify the anatomic features of 1p/19q co-deletion and investigate the predictive values of tumor location and radiological characteristics for the survival of anaplastic oligodendroglial (AO) glioma patients. Voxel-based lesion-symptom mapping (VLSM) analysis was applied to define the brain regions associated with occurrence of 1p/19q co-deletion in a cohort of 206 AO tumor patients (discovery set) treated between May 2009 and September 2013. Retrospectively, the acquired clusters and radiological features were subjected to Kaplan–Meier survival analysis using data from the Chinese Glioma Genome Atlas (validation set) to evaluate their prognostic role in AO patients. The institutional review board approved this study. The right frontal lobe and right anterior insular lobe were specifically associated with high occurrence of 1p/19q co-deletion. For AO tumors not involving these areas, the absence of contrast enhancement predicted longer progression-free (pu2009=u20090.018) and overall survival (pu2009=u20090.020); moreover, in patients with contrast enhancement, edema could stratify the survival outcome (pu2009=u20090.013 for progression-free survival, pu2009=u20090.016 for overall survival). For AO tumors located in the VLSM-identified regions, edema was also able to stratify the survival outcome of patients without contrast enhancement (pu2009=u20090.025 for progression-free survival, pu2009=u20090.028 for overall survival). The 1p/19q co-deletion showed predilection for specific brain regions. According to the tumor involvement of VLSM-identified regions associated with 1p/19q co-deletion, radiological features were predictive for AO patient survival outcomes.

Bioinformatic analysis of gene expression and methylation regulation in glioblastoma

Different gene expression and methylation profiles are identified in glioblastoma (GBM). To screen the differentially expressed genes affected by DNA methylation modification and further investigate their prognostic values for GBMs. We included The Cancer Genome Atlas (TCGA) RNA sequencing (676) and DNA methylation (Illumina Human Methylation 450K; 657) databases to detect the gene expression and methylation profiles. Chinese Glioma Genome Atlas (CGGA) RNA sequencing database and TCGA DNA methylation (Illumina Human Methylation 27K; 283) was included for validation. Gene expression and DNA methylation statues were identified using principal components analysis (PCA). A total of 3365 differentially expressed genes were identified. Among them, 2940 genes showed low methylation and high expression, while 425 genes showed high methylation and low expression in GBMs. An eight-gene (C9orf64, OSMR, MDK, MARVELD1, PTRF, MYD88, BIRC3, RPP25) signature was established to divide GBM patients into two groups based on the cut-off point (27.24). The high risk group had shorter overall survival (OS) than low risk group (median OS 15.77 vs. 10.61 months; Pu2009=u20090.0002). Moreover, the different clinical and molecular features were shown between two groups. These findings could be validated in additional datasets. The differentially expressed genes affected by DNA methylation modification were detected. Our results showed that the eight-gene signature has independently prognostic value for GBM patients.

Long noncoding RNA LINC00152 is a potential prognostic biomarker in patients with high-grade glioma

To investigate the role of LINC00152 in high‐grade glioma (HGG).