Date Published: December 6, 2016
Publisher: Public Library of Science
Author(s): Brian J. Reon, Jordan Anaya, Ying Zhang, James Mandell, Benjamin Purow, Roger Abounader, Anindya Dutta, Elaine Rene Mardis
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.
Partial Text: Malignant gliomas are the most common aggressive primary brain tumor, with nearly 23,000 new cases diagnosed each year in the US . The most aggressive malignant gliomas, anaplastic astrocytoma and glioblastoma multiforme (GBM), have 5-y survival rates of 23% and 5%, respectively. World Health Organization grade II and III gliomas are less aggressive than grade IV glioblastomas (GBMs), and have been grouped together by The Cancer Genome Atlas (TCGA) as lower grade gliomas (LGGs). Once thought to be a single disease, GBMs are now 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]. Importantly, these subtypes are associated with differing clinical outcomes, including varying responses to intensive therapy and differences in overall survival . Similar to GBMs, LGGs can be categorized into distinct subtypes, IDH1/2 mut, IDH1/2 mut 1p19q codeletion, and IDH1/2 wt, based on IDH1/2 mutational status and the presence of a codeletion of 1p19q . Each subtype has distinct clinical phenotypes, with the IDH1/2 wt subtype being the most aggressive and dissimilar to the other LGG subtypes [4,5]. Although knowledge of tumor subtype has clinical utility, the best prognostic indicator for patients with glial tumors is the mutational status of IDH1 and IDH2 . In LGGs, patients with wild-type IDH1/2 have a median survival of 1.7 y, while those with mutant IDH1/2 have a median survival between 6.3 and 8.0 y. In GBMs, the corresponding median survival estimates are 1.1 and 2.1 y for wild-type and mutant IDH1/2, respectively .
Our analysis of RNA-seq data for grade II, III, and IV brain tumors and normal brain tissue has identified hundreds of dysregulated lncRNAs in glial tumors, many of which are associated with tumor subtype or mutational status. Using Cox regression, we identified a panel of 64 lncRNAs that are associated with survival in LGG patients. We also identified lncRNAs that are similarly associated with prognosis in each GBM subtype and found remarkably little overlap of prognostic lncRNAs between GBM subtypes.