Each year, over 16,000 patients die from malignant brain cancer in the US. Long noncoding RNAs (lncRNAs) have recently been shown to play critical roles in regulating neurogenesis and brain tumor progression. To better understand the role of lncRNAs in brain cancer, we performed a global analysis to identify and characterize all annotated and novel lncRNAs in both grade II and III gliomas as well as grade IV glioblastomas (glioblastoma multiforme [GBM]).
Researchers from the University of Virginia determined the expression of all lncRNAs in over 650 brain cancer and 70 normal brain tissue RNA sequencing datasets from The Cancer Genome Atlas (TCGA) and other publicly available datasets. They identified 611 induced and 677 repressed lncRNAs in glial tumors relative to normal brains. Hundreds of lncRNAs were specifically expressed in each of the three lower grade glioma (LGG) subtypes (IDH1/2 wt, IDH1/2 mut, and IDH1/2 mut 1p19q codeletion) and the four subtypes of GBMs (classical, mesenchymal, neural, and proneural). Overlap between the subtype-specific lncRNAs in GBMs and LGGs demonstrated similarities between mesenchymal GBMs and IDH1/2 wt LGGs, with 2-fold higher overlap than would be expected by random chance. Using a multivariate Cox regression survival model, the researchers identified 584 and 282 lncRNAs that were associated with a poor and good prognosis, respectively, in GBM patients. They developed a survival algorithm for LGGs based on the expression of 64 lncRNAs that was associated with patient prognosis in a test set (hazard ratio [HR] = 2.168, 95% CI = 1.765–2.807, p < 0.001) and validation set (HR = 1.921, 95% CI = 1.333–2.767, p < 0.001) of patients from TCGA.
Identification of novel lncRNAs in glial tumors and normal brain RNA-seq samples
(A) Overview of analysis pipeline for identifying novel lncRNAs and determining their associations with clinically relevant phenotypes. (B) Cumulative distribution function plot of CPAT scores demonstrates that the majority of novel transcripts are predicted to not code for proteins (CPAT score < 0.5242). (C) Metagene plot of H3K4me3 ChIP-seq data from U87 cell samples shows enrichment in promoters of protein-coding genes and novel lncRNAs but not in a randomized genomic control. GBM, glioblastoma multiforme; LGG, lower grade glioma; lncRNA, long noncoding RNA; RNA-seq, RNA sequencing