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. 2017 Feb 14;8(7):11517-11529.
doi: 10.18632/oncotarget.14076.

Characterization of RNA Editome in Primary and Metastatic Lung Adenocarcinomas

Affiliations
Free PMC article

Characterization of RNA Editome in Primary and Metastatic Lung Adenocarcinomas

Lihua Peng et al. Oncotarget. .
Free PMC article

Abstract

RNA editing results in post-transcriptional modification and could potentially contribute to carcinogenesis. However, RNA editing in advanced lung adenocarcinomas has not yet been studied. Based on whole genome and transcriptome sequencing data, we identified 1,071,296 RNA editing events from matched normal, primary and metastatic samples contributed by 24 lung adenocarcinoma patients, with 91.3% A-to-G editing on average, and found significantly more RNA editing sites in tumors than in normal samples. To investigate cancer relevant editing events, we detected 67,851 hyper-editing sites in primary and 50,480 hyper-editing sites in metastatic samples. 46 genes with hyper-editing in coding regions were found to result in amino acid alterations, while hundreds of hyper-editing events in non-coding regions could modulate splicing or gene expression, including genes related to tumor stage or clinic prognosis. Comparing RNA editome of primary and metastatic samples, we also discovered hyper-edited genes that may promote metastasis development. These findings showed a landscape of RNA editing in matched normal, primary and metastatic tissues of lung adenocarcinomas for the first time and provided new insights to understand the molecular characterization of this disease.

Keywords: RNA editing; hyper-editing; lung adenocarcinoma; metastatic; primary.

Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Summary of RNA editing events in adjacent normal, primary and metastatic samples from 24 patients
A. Circos plot depicting the landscape of RNA editing in lung adenocarcinoma. The outermost circle shows the samples for each patient and the numbers stand for the patient ID. Red, green and blue depict normal, primary and metastatic samples, respectively. The (i) and (ii) circle display the editing rate and the proportion of editing type for each sample, respectively. The (iii) and (iv) circle denote the distribution of editing sites in different genomic regions ((iii): intronic, UTR3, UTR5 etc; innermost: Alu and non-Alu). B. Comparison of ADAR family gene expression among adjacent normal, primary and metastatic samples. Red, green and blue points depict normal, primary and metastatic samples, respectively, and lines are drawn to connect samples from the same patient. **, P < 0.01; *, P < 0.05; measured by paired t-test.
Figure 2
Figure 2. Comparison of hyper-editing sites in CDS regions between primary and metastatic samples
A. The distribution of hyper-editing sites in CDS regions in each sample. B-D. Histograms showing the proportion of editing types (B), the proportion of Alu region (C) and the proportion of mutation types (D) of hyper-editing sites in CDS regions between primary and metastatic samples. E. The proportion of the cancer-related genes with non-synonymous A -> G hyper-editing sites or with non-synonymous SNV.
Figure 3
Figure 3. Hyper-editing induced splicing aberration of HMOX2
A. The average RNA-seq read coverage and junction counts are shown. Three red vertical lines in exon3 represent three A -> G hyper-editing sites (from left to right, 4533677, 4533713 and 4533730 in chr16) predicted to affect splicing. Samples with the total number of the splice junction reads supporting J2, J3 and J4 less than 10 are excluded. B and C. Comparison of PSI (B) and expression of exon3 (C) in HMOX2 between two subgroups: tumor samples with at least one of the three hyper-editing sites in HMOX2 (“+”) versus those with none (“-”). Wilcoxon rank sum test was used. D. Box plot showing the expression levels of the corresponding transcript between “+” and “-” groups. P value was calculated by t-test. E. The correlation between the editing index of exon 3 and PSI. Pearson's product-moment correlation was used.
Figure 4
Figure 4. Functional analysis of CTC1 with hyper-editing
A. The editing levels of the deleterious site (chr17:8130348) in CTC1 among normal, primary and metastatic samples. B. The expression of CTC1 among three sample groups. C. The correlation between the editing level of chr17:8130348 and the expression of CTC1. D. CTC1 expression versus tumor stages (P value was calculated by the t-test). E. Kaplan-Meier survival curves showing the relationship between recurrence-free survival probability and CTC1 expression (low: less than median; high: greater than median).
Figure 5
Figure 5. Hyper-editing and differential gene expression
A. Differential expression of VHL between edit+ and edit- primary samples. B. Differential expression of GNE between edit+ and edit- primary samples. C. GNE expression versus tumor stages D. Kaplan-Meier survival curves showing the relationship between recurrence-free survival probability and GNE expression. E. Differential expression of MAPK13 in edit+ and edit- groups for primary and metastatic samples. P values are calculated by t-test.

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