m6A methylation regulators as predictors for treatment of advanced urothelial carcinoma with anti-PDL1 agent

PURPOSE: Immune checkpoint blockade agents were shown to provide a survival advantage in urothelial carcinoma, while some patients got minimal benefit or side effects. Therefore, we aimed to investigate the prognostic value of m6A methylation regulators, and developed a nomogram for predicting the response to atezolizumab in urothelial carcinoma patients. METHODS: A total of 298 advanced urothelial carcinoma patients with response data in the IMvigor210 cohort were included. Differential expressions of 23 m6A methylation regulators in different treatment outcomes were conducted. Subsequently, a gene signature was developed in the training set using the least absolute shrinkage and selection operator (LASSO) regression. Based on the multivariable logistic regression, a nomogram was constructed by incorporating the gene signature and independent clinicopathological predictors. The performance of the nomogram was assessed by its discrimination, calibration, and clinical utility with internal validation. RESULTS: Six m6A methylation regulators, including IGF2BP1, IGF2BP3, YTHDF2, HNRNPA2B1, FMR1, and FTO, were significantly differentially expressed between the responders and non-responders. These six regulators were also significantly correlated with the treatment outcomes. Based on the LASSO regression analysis, the gene signature consisting of two selected m6A methylation regulators (FMR1 and HNRNPA2B1) was constructed and showed favorable discrimination. The nomogram integrating the gene signature, TMB, and PD-L1 expression on immune cells, showed favorable calibration and discrimination in the training set (AUC 0.768), which was confirmed in the validation set (AUC 0.755). Decision curve analysis confirmed the potential clinical usefulness of the nomogram. CONCLUSIONS: This study confirmed the prognostic value of FMR1 and HNRNPA2B1, and constructed a nomogram for individualized prediction of the response to atezolizumab in patients with urothelial carcinoma, which may aid in making treatment strategies.