Computational Analysis of RNA Editing in Human Cancer

Discoveries of several oncogenic and tumor-suppressive RNA editing sites haverevealed critical roles of editing in cancer and led to the detection of large-scale aberrations in tumors depending on cancer type. Yet, how these abnormal editing events arise, their contributions to tumor development and spread, and the cancer editomes in individual cell types are generally unknown. In this dissertation, we investigated the functional consequences of altered editing in tumors from the level of bulk tissues to single cells. Expanding upon examples of individual editing sites that promote tumormetastasis, we probed the global editing differences between epithelial and mesenchymal phenotypes in multiple cancer types. Supported by experimental validations, differential editing sites were found to affect mRNA abundance of immune response genes. Furthermore, we identified a novel mechanism of editing-dependent stabilization involving ILF3. Next, we analyzed RNA editing profiles of single cells and individual cell types inlung cancer. Cancer cells were distinctly hyperedited compared to other cell types in the tumor microenvironment. Gene ontology enrichment analyses further suggested celltype specificity of differential editing. As we observed that cancer-specific editing correlated with features of immune suppression and overall survival, increased editing levels in cancer cells may support tumor progression by repressing innate immune responses. Prompted by the apparently diverse contributions of editing to tumor immunity,we sought to identify dsRNA editing candidates that may indicate response to immune checkpoint blockade treatment in melanoma patients. Notably, this analysis revealed the strong candidate dsRNAs that were also correlated with interferon stimulation signatures in lung cancer. Underlying the observed dsRNA associations with treatment response and survival is likely enhanced innate immune signaling activated by unedited dsRNAs