Abstract
BackgroundEach 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]).Methods and FindingsWe 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. We 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, we identified 584 and 282 lncRNAs that were associated with a poor and good prognosis, respectively, in GBM patients. We 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. The main limitations of this study are that further work is needed to investigate the clinical relevance of our findings, and that validation in an independent dataset is needed to determine the robustness of our survival algorithm.ConclusionsThis work identifies a panel of lncRNAs that appear to be prognostic in gliomas and provides a critical resource for future studies examining the role of lncRNAs in brain cancers.
Highlights
Malignant gliomas are the most common aggressive primary brain tumor, with nearly 23,000 new cases diagnosed each year in the US [1]
We developed a survival algorithm for lower grade glioma (LGG) based on the expression of 64 long noncoding RNA (lncRNA) that was associated with patient prognosis in a test set and validation set (HR = 1.921, 95% CI = 1.333–2.767, p < 0.001) of patients from The Cancer Genome Atlas (TCGA)
This work identifies a panel of lncRNAs that appear to be prognostic in gliomas and provides a critical resource for future studies examining the role of lncRNAs in brain cancers
Summary
Malignant gliomas are the most common aggressive primary brain tumor, with nearly 23,000 new cases diagnosed each year in the US [1]. The most aggressive malignant gliomas, anaplastic astrocytoma and glioblastoma multiforme (GBM), have 5-y survival rates of 23% and 5%, respectively. Once thought to be a single disease, GBMs are recognized as having a considerable level of intertumor heterogeneity, and studies have found that GBMs can be subdivided into four subtypes, proneural, neural, classical, and mesenchymal, based on their transcriptional profile [2,3]. These subtypes are associated with differing clinical outcomes, including varying responses to intensive therapy and differences in overall survival [3]. 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])
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