RNA modification writers influence tumor microenvironment in gastric cancer and prospects of targeted drug therapy

Abstract

Background: RNA adenosine modifications are crucial for regulating RNA levels. N6-methyladenosine (m6A), N1-methyladenosine (m1A), adenosine-to-inosine RNA editing, and alternative polyadenylation (APA) are four major RNA modification types. Methods: We evaluated the altered mRNA expression profiles of 27 RNA modification enzymes and compared the differences in tumor microenvironment (TME) and clinical prognosis between two RNA modification patterns using unsupervised clustering. Then, we constructed a scoring system, WM_score, and quantified the RNA modifications in patients of gastric cancer (GC), associating WM_score with TME, clinical outcomes, and effectiveness of targeted therapies. Results: RNA adenosine modifications strongly correlated with TME and could predict the degree of TME cell infiltration, genetic variation, and clinical prognosis. Two modification patterns were identified according to high and low WM_scores. Tumors in the WM_score-high subgroup were closely linked with survival advantage, CD4- T-cell infiltration, high tumor mutation burden, and cell cycle signaling pathways, whereas those in the WM_score-low subgroup showed strong infiltration of inflammatory cells and poor survival. Regarding the immunotherapy response, a high WM_score showed a significant correlation with PD-L1 expression, predicting the effect of PD-L1 blockade therapy. Conclusion: The WM_scoring system could facilitate scoring and prediction of GC prognosis.