Genetic landscape of long noncoding RNA (lncRNAs) in glioblastoma: identification of complex lncRNA regulatory networks and clinically relevant lncRNAs in glioblastoma.

// Yashna Paul 1, * , Sannu Thomas 1, * , Vikas Patil 1, 5, * , Naveen Kumar 1 , Baisakhi Mondal 1 , Alangar S. Hegde 2 , Arimappamagan Arivazhagan 3 , Vani Santosh 4 , Kulandaivelu Mahalingam 5 and Kumaravel Somasundaram 1 1 Department of Microbiology and Cell Biology, Indian Institute of Science, 560012 Bangalore, India 2 Sri Satya Sai Institute of Higher Medical Sciences, 560066 Bangalore, India 3 Department of Neurosurgery, National Institute of Mental Health and Neuro Sciences, 560029 Bangalore, India 4 Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, 560029 Bangalore, India 5 Department of Bio-Medical Sciences, School of Biosciences and Technology, VIT University, 632014 Vellore, India * These authors contributed equally to this work Correspondence to: Kumaravel Somasundaram, email: ksomasundaram1@gmail.com Keywords: lncRNA; glioblastoma; ceRNA; ANRIL; CDKN2A-AS1 Received: November 26, 2017      Accepted: April 20, 2018      Published: July 03, 2018 ABSTRACT The major part of the genome that was previously called junk DNA has been shown to be dynamically transcribed to produce non-coding RNAs. Among them, the long non-coding RNAs (lncRNA) play diverse roles in the cellular context and are therefore involved in various diseases like cancer. LncRNA transcript profiling of glioblastoma ( n = 19) and control brain samples ( n = 9) identified 2,774 and 5,016 lncRNAs to be upregulated and downregulated in GBMs respectively. Correlation analysis of differentially regulated lncRNAs with mRNA and lncRNA identified several lncRNAs that may potentially regulate many tumor relevant mRNAs and lncRNAs both at nearby locations ( cis ) and far locations ( trans ). Integration of our data set with TCGA GBM RNA-Seq data ( n = 172) revealed many lncRNAs as a host as well as decoy for many tumor regulated miRNAs. The expression pattern of seven lncRNAs- HOXD-AS2, RP4-792G4.2, CRNDE, ANRIL, RP11-389G6.3, RP11-325122.2 and AC123886.2 was validated by TCGA RNA-Seq data and RT-qPCR. Silencing ANRIL, a GBM upregulated lncRNA, inhibited glioma cell proliferation and colony growth. Cox regression analysis identified several prognostic lncRNAs. An lncRNA risk score derived from five lnRNAs-RP6-99M1.2, SOX21-AS1, CTD-2127H9.1, RP11-375B1.3 and RP3-449M8.9 predicted survival independent of all other markers. Multivariate cox regression analysis involving G-CIMP, IDH1 mutation, MGMT promoter methylation identified lncRNA risk score to be an independent poor predictor of GBM survival. The lncRNA risk score also stratified GBM patients into low and high risk with significant survival difference. Thus our study demonstrates the importance of lncRNA in GBM pathology and underscores the potential possibility of targeting lncRNA for GBM therapy.