Exploring the Effect of Differentially Expressed Long Non-coding RNAs Driven by Copy Number Variation on Competing Endogenous RNA Network by Mining Lung Adenocarcinoma Data

Abstract

Lung cancer is the first cause of cancer death, and gene copy number variation (CNV) is a vital cause of lung cancer progression. Prognosis prediction of patients followed by medication guidance by detecting CNV of lung cancer is emerging as a promising precise treatment in the future. In this paper, the differences in CNV and gene expression between cancer tissue and normal tissue of lung adenocarcinoma (LUAD) from The Cancer Genome Atlas Lung Adenocarcinoma data set were firstly analyzed, and greater differences were observed. Furthermore, CNV-driven differentially expressed long non-coding RNAs (lncRNAs) were screened out, and then, a competing endogenous RNA (ceRNA) regulatory network related to the gene CNV was established, which involved 9 lncRNAs, seven microRNAs, and 178 downstream messenger RNAs (mRNAs). Pathway enrichment analyses sequentially performed revealed that the downstream mRNAs were mainly enriched in biological pathways related to cell division, DNA repair, and so on, indicating that these mRNAs mainly affected the replication and growth of tumor cells. Besides, the relationship between lncRNAs and drug effects was explored based on previous studies, and it was found that LINC00511 and LINC00942 in the CNV-associated ceRNA network could be used to determine tumor response to drug treatment. As examined, the drugs affected by these two lncRNAs mainly targeted metabolism, target of rapamycin signaling pathway, phosphatidylinositol-3-kinase signaling pathway, epidermal growth factor receptor signaling pathway, and cell cycle. In summary, the present research was devoted to analyzing CNV, lncRNA, mRNA, and microRNA of lung cancer, and nine lncRNAs that could affect the CNV-associated ceRNA network we constructed were identified, two of which are promising in determining tumor response to drug treatment.

Keywords: LUAD; TCGA; ceRNA network; copy number variation; lncRNA.

Figure 1

Overall workflow of this study.

Figure 2

Differential analysis results. (A) Volcano plot of DElncRNAs; (B) volcano plot of DEmiRNAs; (C) volcano plot of DEmRNAs; green dots represent differentially downregulated genes, and red dots represent differentially upregulated genes.

Figure 3

Filtering of CNV-driven DElncRNAs. (A) Circle map of lncRNA CNVs in LUAD (black dots represent duplication CNVs, and blue dots represent deletion CNVs; (B) Venn diagram filters upregulated lncRNAs with duplication CNVs; (C) Venn diagram filters downregulated lncRNAs with deletion CNVs.

Figure 4

Heatmaps of RNAs in CNV-associated ceRNA network. (A) Heatmap of lncRNAs in CNV-associated ceRNA network; (B) heatmap of miRNAs in CNV-associated ceRNA network; (C) heatmap of mRNAs in CNV-associated ceRNA network.

Figure 5

Overview of CNV-associated ceRNA network and CNVs of lncRNAs. (A) Interaction between different RNAs in the CNV-associated ceRNA network; the shape of each node represents the type of RNA (squares represent lncRNAs, swallowtail quadrilaterals represent miRNAs, and circles represent mRNAs), and the color of each node represents the regulation type (the red represents upregulated, and the blue represents downregulated); (B,C) chromosomal view of amplification and deletion peaks between tumor and normal tissue; G-score (top) and p-value (bottom) were calculated by GISTIC2; right axis represents chromosomal position, and examples of CNV-driven DElncRNAs located in the peaks are labeled.

Figure 6

Functional enrichment analyses of mRNAs in CNV-associated ceRNA network. (A) Gene Ontology annotation of mRNAs in the CNV-associated ceRNA network; (B) Kyoto Encyclopedia of Genes and Genomes pathway enrichment of mRNAs in the CNV-associated ceRNA network.

Figure 7

Association between expression and CNV of lncRNAs. Gray box represents the normal group, red box represents patients with amplification CNVs, and blue box represents patients with deletion CNVs.

Figure 8

Survival analysis of the 9 lncRNAs in CNV-associated ceRNA network. Gray line represents the normal group, red line represents patients with amplification CNVs, and blue line represents patients with deletion CNVs.