Clinical Relevance of Noncoding Adenosine-to-Inosine RNA Editing in Multiple Human Cancers

Abstract

© 2019 by American Society of Clinical Oncology. PURPOSE RNA editing is a post-transcriptional process that alters the nucleotide sequences of certain transcripts, in vertebrate most often converting adenosines to inosines. Multiple studies have recently implicated RNA editing in cancer development; however, most studies have focused on recoding RNA editing events. The function and clinical relevance of noncoding RNA (ncRNA) editing events in cancers have not been systematically examined. PATIENTS AND METHODS We improved our previously published pipeline to identify ncRNA editing sites from four human cancers: liver hepatocellular carcinoma, lung adenocarcinoma, kidney renal clear-cell carcinoma, and thyroid carcinoma. We then developed multiple advanced statistical models to identify significantly differential edited (DE) sites between tumor and normal samples and clinical relevance ncRNA editing sites, as well as to investigate the association between gene expression, ncRNA editing, and microRNAs. Finally, we validated computational results with experiments. RESULTS We identified 3,788 ncRNA editing sites of high confidence from the four cancers. We found thousands of DE sites which had distinct profiles across the four cancers. In kidney cancer, which had the largest uncensored survival data among the four cancers, 80 DE sites were significantly associated with patient survival. We identified 3 untranslated region (UTR) RNA editing sites that can affect gene expression, either independent of or by working with microRNAs. We validated that the 3UTR RNA editing sites in CWF19L1 and F11R genes resulted in increased protein levels and that alterations of the expression of the two genes affected the proliferation of human embryonic kidney cells. CONCLUSION On the basis of our computational and experimental results, we hypothesize that 3UTR editing sites may affect their host gene expression, thereby affecting cell proliferation.