title: Differential correlation analysis of glioblastoma reveals immune ceRNA interactions predictive of patient survival.
abstract: BACKGROUND
  Recent studies illuminated a novel role of microRNA (miRNA) in the competing endogenous RNA (ceRNA) interaction: two genes (ceRNAs) can achieve coexpression by competing for a pool of common targeting miRNAs. Individual biological investigations implied ceRNA interaction performs crucial oncogenic/tumor suppressive functions in glioblastoma multiforme (GBM). Yet, a systematic analysis has not been conducted to explore the functional landscape and prognostic significance of ceRNA interaction.
  
  
  RESULTS
  Incorporating the knowledge that ceRNA interaction is highly condition-specific and modulated by the expressional abundance of miRNAs, we devised a ceRNA inference by differential correlation analysis to identify the miRNA-modulated ceRNA pairs. Analyzing sample-paired miRNA and gene expression profiles of GBM, our data showed that this alternative layer of gene interaction is essential in global information flow. Functional annotation analysis revealed its involvement in activated processes in brain, such as synaptic transmission, as well as critical tumor-associated functions. Notably, a systematic survival analysis suggested the strength of ceRNA-ceRNA interactions, rather than expressional abundance of individual ceRNAs, among three immune response genes (CCL22, IL2RB, and IRF4) is predictive of patient survival. The prognostic value was validated in two independent cohorts.
  
  
  CONCLUSIONS
  This work addresses the lack of a comprehensive exploration into the functional and prognostic relevance of ceRNA interaction in GBM. The proposed efficient and reliable method revealed its significance in GBM-related functions and prognosis. The highlighted roles of ceRNA interaction provide a basis for further biological and clinical investigations.
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.|Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, No. 1, Section 4, Roosevelt Rd., Taipei, 10617, Taiwan.|Department of Medical Research, Taichung Veterans General Hospital, No. 1650, Section 4, Taiwan Blvd., Xitun District, Taichung City, 40705, Taiwan.
authors.forename: Yu-Chiao
authors.initials: YC
authors.lastname: Chiu
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, No. 1650, Section 4, Taiwan Blvd., Xitun District, Taichung City, 40705, Taiwan.
authors.forename: Li-Ju
authors.initials: LJ
authors.lastname: Wang
authors.affiliation: Department of Public Health, National Taiwan University, Taipei, 10055, Taiwan.
authors.forename: Tzu-Pin
authors.initials: TP
authors.lastname: Lu
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, No. 1650, Section 4, Taiwan Blvd., Xitun District, Taichung City, 40705, Taiwan. thsiao@vghtc.gov.tw.
authors.forename: Tzu-Hung
authors.initials: TH
authors.lastname: Hsiao
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, No. 1, Section 4, Roosevelt Rd., Taipei, 10617, Taiwan. chuangey@ntu.edu.tw.|Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, 10055, Taiwan. chuangey@ntu.edu.tw.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Chuang
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. ChenY8@uthscsa.edu.|Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX, 78229, USA. ChenY8@uthscsa.edu.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D054422:Chemokine CCL22 / Q000235:genetics; D004843:Epistasis, Genetic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics; D035683:MicroRNAs / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism*; D016019:Survival Analysis; D000099218:Interferon Regulatory Factor-4
chemical_list: D054422:Chemokine CCL22; D050835:Interferon Regulatory Factors; D053646:Interleukin-2 Receptor beta Subunit; D035683:MicroRNAs; D012334:RNA, Neoplasm; D000099218:Interferon Regulatory Factor-4; C515482:CCL22 protein, human; C508020:IL2RB protein, human
keywords: Competing endogenous RNA; Differential correlation analysis; Glioblastoma multiforme; Immune genes; Survival prediction