Molecular Context of ADAR-Mediated Editing of Coding RNA in Colorectal and Lung Cancers

TL;DR

This study explores how RNA editing by ADAR enzymes differs in colorectal and lung cancers compared to healthy tissues, revealing significant changes in editing levels and their molecular implications.

Contribution

A rapid method for assessing ADAR editing using 24 coding region positions is developed and applied to cancer and healthy tissues.

Findings

ADAR-mediated RNA editing levels are significantly lower in colorectal and lung cancers compared to healthy controls.

ADAR editing correlates with 740 molecular pathways, including extracellular matrix organization and RAS-MAPK axis, and inversely with DNA repair and apoptosis pathways.

Abstract

RNA editing is a critical post-transcriptional modification that contributes to transcriptomic and proteomic diversity. The most common A-to-I (recognized as G) RNA editing enzymes are adenosine deaminases acting on RNA 1 and 2 (ADAR1 and ADAR2, respectively), which mediate alterations across all regions of mRNA molecules. However, a systematic cross-tissue view of RNA editing and its molecular correlates is still lacking. Here, we developed a rapid method for ADAR editing assessment based on 24 frequently edited positions in coding regions, which enables faster estimation of RNA editing levels than previous methods. We applied this metric to assess RNA editing in normal and cancerous lung and colorectal tissues. We analyzed RNA and whole exome sequencing profiles of experimental 172 colorectal and 144 lung cancer samples, and literature 646 colorectal and 1037 lung cancer samples. We also examined two types of control tissues: tumor-matched normal tissues (51 colorectal and 108 lung samples) and healthy tissues (6 colorectal and 7 lung samples). Overall ADAR-mediated RNA editing levels were ~2.9- and ~4.7-fold higher in healthy controls than in colorectal and lung cancers, respectively. In addition to their well-known association with immune cells, we identified positive correlations of ADAR editing with 740 molecular pathways including those responsible for extracellular matrix organization, RAS-MAPK axis and G2/M phase cell cycle arrest, and negative—with 139 pathways responsible for DNA repair, apoptosis, expression of transposable elements, and other factors.

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