Using integrated analysis from multicentre studies to identify RNA methylation-related lncRNA risk stratification systems for glioma.

BACKGROUND: N6-methyladenosine (m6A), 5-methylcytosine (m5C) and N1-methyladenosine (m1A) are the main RNA methylation modifications involved in the progression of cancer. However, it is still unclear whether RNA methylation-related long noncoding RNAs (lncRNAs) affect the prognosis of glioma. METHODS: We summarized 32 m6A/m5C/m1A-related genes and downloaded RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify differentially expressed (DE-) RNA methylation-related lncRNAs in order to construct a prognostic signature of glioma and in order to determine their correlation with immune function, immune therapy and drug sensitivity. In vitro and in vivo assays were performed to elucidate the effects of RNA methylation-related lncRNAs on glioma. RESULTS: A total of ten RNA methylation-related lncRNAs were used to construct a survival and prognosis signature, which had good independent prediction ability for patients. It was found that the high-risk group had worse overall survival (OS) than the low-risk group in all cohorts. In addition, the risk group informed the immune function, immunotherapy response and drug sensitivity of patients with glioma in different subgroups. Knockdown of RP11-98I9.4 and RP11-752G15.8 induced a more invasive phenotype, accelerated cell growth and apparent resistance to temozolomide (TMZ) both in vitro and in vivo. We observed significantly elevated global RNA m5C and m6A levels in glioma cells. CONCLUSION: Our study determined the prognostic implication of RNA methylation-related lncRNAs in gliomas, established an RNA methylation-related lncRNA prognostic model, and elucidated that RP11-98I9.4 and RP11-752G15.8 could suppress glioma proliferation, migration and TMZ resistance. In the future, these RNA methylation-related lncRNAs may become a new choice for immunotherapy of glioma.

Development and validation of a pyroptosis-related genes signature for risk stratification in gliomas.

Background: Glioma is a highly heterogeneous disease, causing the prognostic prediction a challenge. Pyroptosis, a programmed cell death mediated by gasdermin (GSDM), is characterized by cell swelling and the release of inflammatory factors. Pyroptosis occurs in several types of tumor cells, including gliomas. However, the value of pyroptosis-related genes (PRGs) in the prognosis of glioma remains to be further clarified. Methods: In this study, mRNA expression profiles and clinical data of glioma patients were acquired from TCGA and CGGA databases, and one hundred and eighteen PRGs were obtained from the Molecular Signatures Database and GeneCards. Then, consensus clustering analysis was performed to cluster glioma patients. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to establish a polygenic signature. Functional verification of the pyroptosis-related gene GSDMD was achieved by gene knockdown and western blotting. Moreover, the immune infiltration status between two different risk groups were analyzed through the "gsva" R package. Results: Our results demonstrated that the majority of PRGs (82.2%) were differentially expressed between lower-grade gliomas (LGG) and glioblastoma (GBM) in the TCGA cohort. In univariate Cox regression analysis, eighty-three PRGs were shown to be associated with overall survival (OS). A five-gene signature was constructed to divide patients into two risk groups. Compared with patients in the low-risk group, patients in the high-risk group had obviously shorter OS (p < 0.001). Also, we found that the high-risk group showed a higher infiltrating score of immune cells and immune-related functions. Risk score was an independent predictor of OS (HR > 1, p < 0.001). Furthermore, knockdown of GSDMD decreased the expression of IL-1ß and cleaved caspase-1. Conclusion: Our study constructed a new PRGs signature, which can be used to predict the prognosis of glioma patients. Targeting pyroptosis might serve as a potential therapeutic strategy for glioma.

An Integrative Framework of Heterogeneous Genomic Data for Cancer Dynamic Modules Based on Matrix Decomposition.

Cancer progression is dynamic, and tracking dynamic modules is promising for cancer diagnosis and therapy. Accumulated genomic data provide us an opportunity to investigate the underlying mechanisms of cancers. However, as far as we know, no algorithm has been designed for dynamic modules by integrating heterogeneous omics data. To address this issue, we propose an integrative framework for dynamic module detection based on regularized nonnegative matrix factorization method (DrNMF) by integrating the gene expression and protein interaction network. To remove the heterogeneity of genomic data, we divide the samples of expression profiles into groups to construct gene co-expression networks. To characterize the dynamics of modules, the temporal smoothness framework is adopted, in which the gene co-expression network at the previous stage and protein interaction network are incorporated into the objective function of DrNMF via regularization. The experimental results demonstrate that DrNMF is superior to state-of-the-art methods in terms of accuracy. For breast cancer data, the obtained dynamic modules are more enriched by the known pathways, and can be used to predict the stages of cancers and survival time of patients. The proposed model and algorithm provide an effective integrative analysis of heterogeneous genomic data for cancer progression.

DREAM: a database of experimentally supported protein-coding RNAs and drug associations in human cancer.

The Drug Response Gene Expression Associated Map, also referred as "DREAM" ( http://bio-big-data.cn:8080/DREAM ), is a manually curated database of experimentally supported protein-coding RNAs and drugs associations in human cancers. The current version of the DREAM documents 3048 entries about scientific literatures supported drug sensitivity or drug intervention related protein-coding RNAs from PubMed database and 195 high-throughput microarray data about drug sensitivity or drug intervention related protein-coding RNAs data from GEO database. Each entry in DREAM database contains detailed information on protein-coding RNA, drug, cancer, and other information including title, PubMed ID, journal, publish time. The DREAM database also provides some data visualization and online analysis services such as volcano plot, GO/KEGG enrichment function analysis, and novel drug discovery analysis. We hope the DREAM database should serve as a valuable resource for clinical practice and basic research, which could help researchers better understand the effects of protein-coding RNAs on drug response in human cancers.

An Integrative Framework for Protein Interaction Network and Methylation Data to Discover Epigenetic Modules.

DNA methylation is a critical epigenetic modification that plays an important role in cancers. The available algorithms fail to fully characterize epigenetic modules. To address this issue, we first characterize the epigenetic module as a group of well-connected genes in the protein interaction network and are also co-methylated based on gene methylation profiles. Then, the epigenetic module discovery problem is transformed into an optimization problem. Then, a regularized nonnegative matrix factorization algorithm for methylation modules (RNMF-MM) is presented, where the co-methylation constraint is treated as a regularizer. Using the artificial networks with known module structure, we demonstrate that the proposed algorithm outperforms state-of-the-art approaches in terms of accuracy. On the basis of breast cancer methylation data and protein interaction network, the RNMF-MM algorithm discovers methylation modules that are significantly more enriched by the known pathways than those obtained by other algorithms. These modules serve as biomarkers for predicting cancer stages and estimating survival time of patients. The proposed model and algorithm provide an effective way for the integrative analysis of protein interaction network and methylation data.

Multi-Objective Optimization Algorithm to Discover Condition-Specific Modules in Multiple Networks.

The advances in biological technologies make it possible to generate data for multiple conditions simultaneously. Discovering the condition-specific modules in multiple networks has great merit in understanding the underlying molecular mechanisms of cells. The available algorithms transform the multiple networks into a single objective optimization problem, which is criticized for its low accuracy. To address this issue, a multi-objective genetic algorithm for condition-specific modules in multiple networks (MOGA-CSM) is developed to discover the condition-specific modules. By using the artificial networks, we demonstrate that the MOGA-CSM outperforms state-of-the-art methods in terms of accuracy. Furthermore, MOGA-CSM discovers stage-specific modules in breast cancer networks based on The Cancer Genome Atlas (TCGA) data, and these modules serve as biomarkers to predict stages of breast cancer. The proposed model and algorithm provide an effective way to analyze multiple networks.

Identifying condition-specific modules by clustering multiple networks.

Condition-specific modules in multiple networks must be determined to reveal the underlying molecular mechanisms of diseases. Current algorithms exhibit limitations such as low accuracy and high sensitivity to the number of networks because these algorithms discover condition-specific modules in multiple networks by separating specificity and modularity of modules. To overcome these limitations, we characterize condition-specific module as a group of genes whose connectivity is strong in the corresponding network and weak in other networks; this strategy can accurately depict the topological structure of condition-specific modules. We then transform the condition-specific module discovery problem into a clustering problem in multiple networks. We develop an efficient heuristic algorithm for the Specific Modules in Multiple Networks (SMMN), which discovers the condition-specific modules by considering multiple networks. By using the artificial networks, we demonstrate that SMMN outperforms state-of-the-art methods. In breast cancer networks, stage-specific modules discovered by SMMN are more discriminative in predicting cancer stages than those obtained by other techniques. In pan-cancer networks, cancer-specific modules are more likely to associate with survival time of patients, which is critical for cancer therapy.

Clustering algorithms for detecting functional modules in protein interaction networks.

Protein-Protein Interaction (PPI) networks are believed to be important sources of information related to biological processes and complex metabolic functions of the cell. When studying the workings of a biological cell, it is useful to be able to detect known and predict still undiscovered protein complexes within the cell's PPI networks. Such predictions may be used as an inexpensive tool to direct biological experiments. The increasing amount of available PPI data necessitate a fast, accurate approach to biological complex identification. Because of its importance in the studies of protein interaction network, there are different models and algorithms in identifying functional modules in PPI networks. In this paper, we review some representative algorithms, focusing on the algorithms underlying the approaches and how the algorithms relate to each other. In particular, a comparison is given based on the property of the algorithms. Since the PPI network is noisy and still incomplete, some methods which consider other additional properties for preprocessing and purifying of PPI data are presented. We also give a discussion about the functional annotation and validation of protein complexes. Finally, new progress and future research directions are discussed from the computational viewpoint.