Identification and characterization of ADAR1 mutations and changes in gene expression in human cancers

Abstract

ADAR1 (Adenosine deaminase action on RNA1) is involved in post-transcriptional RNA editing. ADAR1 mutations have been identified in many cancers but its role in tumor formation is still not well understood. Here we used available cancer genomes deposited on CSOMIC and cBioPortal to identify and characterize mutations and changes in ADAR1 expression in cancer cells. We identify several high frequency substitutions including one at R767 which is located in one of the dsRNA interacting domains. In silico protein structure analysis suggest the R767 mutations affect the protein stability and are likely to destabilize interaction with dsRNA. Gene expression analysis shows that in samples with under-expressed ADAR1, there is a statistically significant increase in expression of BLCAP (Bladder Cancer Associated Protein). Although BLCAP was initially identified in bladder cancers, more recent evidence shows that it is a tumor suppressor and BLCAP mutations have been detected in many cancer cells. Epistatic analysis using the cBioPortal mutual exclusivity calculator for the TCGA pan-cancer data shows that co-mutations between ADAR1 and other genes regulated by it are likely in cancer cells except for PTEN, AKT1 and BLCAP. This suggests that when ADAR1 function is impaired, PTEN, AKT1 and BLCAP become essential for survival of cancer cells. We also identified several samples with high mutation burden between ADAR1 and other genes regulated primarily in endometrial cancers. Finally, we show that the deaminase domain is highly conserved in metazoans and mutations within conserved residues do occur in human cancers suggesting that destabilization of the enzyme function is contributing to cancer development.