Analysis of Multi-Layer RNA Modification Patterns for the Characterization of Tumor Immune Microenvironment in...

Background: RNA modifications have emerged as important posttranscriptional changes in multiple tumor cellular processes and tumorigenesis, including hepatocellular carcinoma (HCC). However, the potential roles and the interaction between regulators of RNA modifications and the tumor microenvironment (TME) are unclear in HCC. Methods: The gene expression profiles of 26 RNA modification "writers" were investigated in the TCGA cohort. The unsupervised clustering approach was used to class these RNA modification regulators. The characteristics of immune cell infiltration from TME for each cluster was tested by the CIBERSORT method. Additionally, we established a scoring model to evaluate the RNA modification characteristics of individual tumors. The associations between the scoring model and genetic as well as clinical characteristics, drug sensitivity, and response to immunotherapy were also analyzed. Results: We mapped the somatic mutations and somatic copy number variation of the RNA modification regulators. The expression of all selected regulators was detected, and two modification patterns were identified that featured distinct immune cell infiltration characteristics. Subsequently, we developed a score model (termed as WM-Score model). Furthermore, the survival analysis showed that the WM-Score value was associated with HCC patient prognosis. The results of the ROC curves analysis and multivariate analysis all confirmed that the WM-Score value was strongly associated with anti-cancer drug resistance and therapeutic efficacy of immunotherapy, thus could be used as an independent risk factor in HCC. Conclusion: Our research identified two RNA modification patterns characterized by distinct TME, and the WM-Score model was developed that might serve as reliable prognostic and immunotherapeutic effect predictor of HCC.