Integrative analysis of genomic and epigenomic regulation reveals microRNA regulatory network mediated tumor heterogeneity and immune evasion in lower grade glioma

Abstract

Abstract Background Lower grade glioma (LGG) is the most frequent primary tumors of the central nervous system and has been a major healthcare burden, however, the specific molecular mechanism underlying its initiation and progression remains to be elucidated. Although it is known that microRNAs (miRNAs) are widely involved in the regulation of malignant phenotypes of glioma, the underling mechanism for miRNA dysregulation remains largely unanswered. Methods In the present work, we developed a novel strategy to obtain the genome wide copy number variation (CNV) and promoter DNA methylation (DNAm) data of miRNAs and performed a systematic integrative study for the multi-omics data to identify mechanisms underlying miRNA dysregulation molecular subtyping in LGG. The relationship between LGG subtypes, prognosis, molecular features, tumor immune microenvironment and response to immune therapy was further analyzed. We also developed a prognostic model based on immune-related miRNAs that were differentially expressed between LGG samples. Then, the influence of the prognostic model on the immune microenvironment in LGG was comprehensively analyzed. Results We identify 719 miRNAs whose expression was associated with alterations of copy number variation or promoter methylation. Integrative multi-omics analysis of the copy number and methylation related miRNAs revealed four subtypes with differing prognoses, which were validated with independent cohort data. These glioma subtypes exhibited distinct immune-related characteristics as well as clinical and genetic features. We further screened immune-related miRNAs through investigation of their correlation with immune cell infiltrations and immune microenvironment. By construction of a miRNA regulatory network, we identified candidate miRNAs associated with immune evasion and response to glioma immunotherapy. We finally evaluated the associations between prognosis related miRNAs and immune regulation. Among them, miR-155-5p, miR-196a-5p, miR-196b-5p, miR-200a-3p, miR-503-5p, and miR-15b-5p were validated as immunoevasive biomarkers and to promote cell migration, invasion and proliferation for glioma through in vitro experiments. Conclusions Our study systematically reveals the crosstalk among DNA methylation, copy number variation and miRNA expression for immune regulation in glioma, and could have important implications for patient stratification and development of novel biomarkers for immunotherapy approaches.