Elevated RNA Editing Activity Is a Major Contributor to Transcriptomic Diversity in Tumors

Abstract

Genomic mutations in key genes are known to drive tumorigenesis and have been the focus of much attention in recent years. However, genetic content also may change farther downstream. RNA editing alters the mRNA sequence from its genomic blueprint in a dynamic and flexible way. A few isolated cases of editing alterations in cancer have been reported previously. Here, we provide a transcriptome-wide characterization of RNA editing across hundreds of cancer samples from multiple cancer tissues, and we show that A-to-I editing and the enzymes mediating this modification are significantly altered, usually elevated, in most cancer types. Increased editing activity is found to be associated with patient survival. As is the case with somatic mutations in DNA, most of these newly introduced RNA mutations are likely passengers, but a few may serve as drivers that may be novel candidates for therapeutic and diagnostic purposes.

Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer's disease

“…Recoding by A-to-I editing is a highly regulated process, whereas deregulated recoding has been associated with multiple ailments (Paz et al 2007;Slotkin and Nishikura 2013;Tomaselli et al 2014;Paz-Yaacov et al 2015). Only a few dozen recoding sites are conserved across mammals, and hundreds of human-specific (or primate-specific) sites have been identified, mostly weakly edited Pinto et al 2014;Ramaswami and Li 2014).…”

RNA editing of AZIN1 induces the malignant progression of non-small-cell lung cancers

“…8,9 Recently, several studies systematically characterized the landscape and clinical relevance of RNA editings in a variety of cancers. 10,11 RNA editing is globally controlled by tumor interferon and adenosine deaminase acting on RNA (ADAR) copy number, and both factors are highly prevalent among human cancers. 11,12 The high frequency of a site-specific RNA editing event, which is the serine-toglycine substitution at residue 367 (S367G) in antizyme inhibitor 1 (AZIN1), was uncovered in hepatocellular and esophageal carcinoma.…”

“…10,11 RNA editing is globally controlled by tumor interferon and adenosine deaminase acting on RNA (ADAR) copy number, and both factors are highly prevalent among human cancers. 11,12 The high frequency of a site-specific RNA editing event, which is the serine-toglycine substitution at residue 367 (S367G) in antizyme inhibitor 1 (AZIN1), was uncovered in hepatocellular and esophageal carcinoma. 13,14 Here, we illustrated how AZIN1 RNA editing occurred in NSCLC patients' specimens and cell line models as well as demonstrated the role of ADARmediated AZIN1 RNA editing in NSCLC development.…”

Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers

“…Several studies have characterized the critical role of individual missense A-to-I RNA editing events in cancer development (Chen et al 2013;Galeano et al 2013;Han et al 2014). More recently, we and other groups have systematically characterized the RNA-editing genomic landscape in various cancer types using mRNA-seq data from The Cancer Genome Atlas (TCGA) (Fumagalli et al 2015;Han et al 2015;Paz-Yaacov et al 2015). These studies revealed a large number of dysregulated A-to-I RNA editing events in tumor samples relative to normal samples, many of which show clinically relevant patterns and suggested that, like "driver" somatic mutations, RNA editing events alter the growth of cancer cells and also selectively change drug sensitivity in cell lines consistent with therapeutic relevance in patients.…”