Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer

BackgroundThe four major RNA adenosine modifications, i.e., m(6)A, m(1)A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the writer enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these writers in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown.MethodsWe systematically characterized mRNA expression and genetic alterations of 26 RNA modification writers in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification writers. Subsequently, we constructed the RNA modification writer Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy.ResultsWe demonstrated that multi-layer alterations of RNA modification writer are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. ?In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these writers to aid the clinical benefits of immunotherapy.ConclusionsOur study is the first to ?provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification writers in cancer therapy.

Automated summary

Our study provides a comprehensive analysis of four RNA modifications in CRC and reveals the potential functions of these writers in TME, transcriptional and post-transcriptional events. The study also identifies the therapeutic implications of targeting these writers in cancer therapy, highlighting their potential clinical utility in targeted therapy and immunotherapy.