RNA editing events associated with patient outcome are functionally relevant in many cancer types.
Major finding: RNA editing events associated with patient outcome are functionally relevant in many cancer types.
Approach: A global analysis of RNA editing in 17 tumor types revealed clinically relevant RNA editing events.
Impact: Clinically relevant RNA editing events are potential biomarkers or drug targets.
RNA editing is an evolutionarily conserved post-transcriptional modification of RNA sequences from their genome-encoded sequences, the most common type of which is deamination of adenosine to inosine (A-to-I) catalyzed by members of the adenosine deaminase, RNA-specific (ADAR) family of enzymes. However, the functional consequences of RNA editing, which often occur in noncoding and repetitive genomic regions, have been described only for individual examples in specific cancers. To characterize the global pattern and clinical relevance of A-to-I RNA editing in human cancers, Han and colleagues systematically analyzed A-to-I editing events in The Cancer Genome Atlas RNA-sequencing (RNA-seq) dataset. A large database of reported RNA editing sites, which was curated to remove SNPs and somatic mutations, was used to identify RNA editing signals in 6,236 samples from 17 cancer types. In 12 tumor types, RNA editing sites with significantly differential editing activity between matched tumor and normal samples were characterized. Further analyses revealed that the altered RNA editing patterns in tumors correlated with ADAR1 expression and that a number of nonrandom RNA editing events, subsequently referred to as clinically relevant RNA editing events, correlated with tumor classification and patient survival. Investigation of the distribution of clinically relevant RNA editing events revealed that they were frequently located in noncoding RNAs, nonsynonymous sites, intronic regions, and non-Alu elements. In vitro assays were performed to assess the functional effects of three nonsynonymous clinically relevant RNA editing events identified in multiple cancer types, and it was found that these events increased cell survival and altered drug sensitivity. These results identify the global pattern of clinically relevant RNA editing events across tumor types and normal tissues and demonstrate a potential driver role of RNA editing in cancer.