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Global Transcriptome Analysis of RNA Abundance Regulation by ADAR in Lung Adenocarcinoma
Michael F Sharpnack1, Bin Chen2, Dvir Aran2
1Department of Biomedical Informatics, The Ohio State University, Columbus, OH, United States.
Abstract:
Despite tremendous advances in targeted therapies against lung adenocarcinoma, the majority of patients do not benefit from personalized treatments. A deeper understanding of potential therapeutic targets is crucial to increase the survival of patients. One promising target, ADAR, is amplified in 13% of lung adenocarcinomas and in-vitro studies have demonstrated the potential of its therapeutic inhibition to inhibit tumor growth. ADAR edits millions of adenosines to inosines within the transcriptome, and while previous studies of ADAR in cancer have solely focused on protein-coding edits, >99% of edits occur in non-protein coding regions. Here, we develop a pipeline to discover the regulatory potential of RNA editing sites across the entire transcriptome and apply it to lung adenocarcinoma tumors from The Cancer Genome Atlas. This method predicts that 1413 genes contain regulatory edits, predominantly in non-coding regions. Genes with the largest numbers of regulatory edits are enriched in both apoptotic and innate immune pathways, providing a link between these known functions of ADAR and its role in cancer. We further show that despite a positive association between ADAR RNA expression and apoptotic and immune pathways, ADAR copy number is negatively associated with apoptosis and several immune cell types' signatures.
Insights
Adenosine deaminase acting on RNA (ADAR) targets non-coding regions in lung adenocarcinoma, impacting apoptosis and immune pathways. Understanding these edits offers new therapeutic strategies for cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lung adenocarcinoma treatments remain limited for many patients.
- Adenosine deaminase acting on RNA (ADAR) is a potential therapeutic target, implicated in 13% of lung adenocarcinomas.
- ADAR's role in cancer is primarily studied through protein-coding edits, neglecting non-coding regions where >99% of its edits occur.
Purpose of the Study:
- To develop a comprehensive method for identifying regulatory RNA editing sites across the entire transcriptome.
- To investigate the role of ADAR-mediated RNA editing in lung adenocarcinoma, focusing on non-coding regions.
Main Methods:
- Development of a novel computational pipeline to analyze RNA editing sites.
- Application of the pipeline to lung adenocarcinoma tumor data from The Cancer Genome Atlas (TCGA).
- Analysis of gene enrichment in apoptotic and innate immune pathways based on predicted regulatory edits.
Main Results:
- The pipeline predicted 1413 genes with regulatory ADAR edits, predominantly in non-coding regions.
- Genes with extensive regulatory edits were significantly enriched in apoptosis and innate immune pathways.
- ADAR RNA expression positively correlated with apoptosis and immune pathways, while ADAR copy number showed negative associations.
Conclusions:
- ADAR-mediated RNA editing in non-coding regions plays a significant role in lung adenocarcinoma.
- These edits are linked to critical cancer pathways, including apoptosis and immune response.
- The findings highlight ADAR's complex role in cancer and suggest potential for novel therapeutic interventions targeting RNA editing.
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