A novel integrated gene coexpression analysis approach reveals a prognostic three-transcription-factor signature for glioma molecular subtypes

Background: Glioma is the most common brain tumor and it has very high mortality rate due to its infiltration and heterogeneity. Precise classification of glioma subtype is essential for proper therapeutic treatment and better clinical prognosis. However, the molecular mechanism of glioma is far from clear and the classical classification methods based on traditional morphologic and histopathologic knowledge are subjective and inconsistent. Recently, classification methods based on molecular characteristics are developed with rapid progress of high throughput technology. Methods: In the present study, we designed a novel integrated gene coexpression analysis approach, which involves differential coexpression and differential regulation analysis (DCEA and DRA), to investigate glioma prognostic biomarkers and molecular subtypes based on six glioma transcriptome data sets. Results: We revealed a novel three-transcription-factor signature including AHR, NFIL3 and ZNF423 for glioma molecular subtypes. This three-TF signature clusters glioma patients into three major subtypes (ZG, NG and IG subtypes) which are significantly different in patient survival as well as transcriptomic patterns. Notably, ZG subtype is featured with higher expression of ZNF423 and has better prognosis with younger age at diagnosis. NG subtype is associated with higher expression of NFIL3 and AHR, and has worse prognosis with elder age at diagnosis. According to our inferred differential networking information and previously reported signalling knowledge, we suggested testable hypotheses on the roles of AHR and NFIL3 in glioma carcinogenesis. Conclusions: With so far the least biomarkers, our approach not only provides a novel glioma prognostic molecular classification scheme, but also helps to explore its dysregulation mechanisms. Our work is extendable to prognosis-related classification and signature identification in other cancer researches.