Alteration of METTL3 Predicts Response to Neoadjuvant Chemotherapy in Muscle - Invasive Bladder Cancer

Background: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy is the current gold standard treatment for muscle-invasive bladder cancer (MIBC). Nonetheless, some MIBC patients showed limited pathological response to NAC. Methods: Herein, we used the whole-exome sequencing to identify the mutation profiles in MIBC to predict the NAC response. Findings: In the discovery cohort, somatic mutation of genes CDH9, METTL3 and PTPRH particularly occurred in NAC responder, signifying that these mutations were potential predictor in the pathological response to NAC. Furthermore, somatic mutation of CCDC141 was exclusively identified in NAC nonresponders, signifying that this mutation was responsible for the NAC resistance. Pathway enrichment analysis revealed that distinct pathway regulations based on mutational profiles of NAC responders and nonresponders. Compared to other cohort studies, the somatic mutations of CDH9, METTL3 and PTPRH were enriched among NAC responders while somatic mutation of CCDC141 was enriched in NAC nonresponders from validation cohort. Furthermore, survival analysis revealed that patients expressing mutated METTL3 has a prolonged overall survival and disease/progression-free survival than patients acquiring wild-type METTL3. Interpreation: In short, somatic mutation of METTL3 can be a potential predictive biomarker of NAC response in MIBC patients. Funding Statement: This work was supported by the Basic Scientific Research Operating Expenses for Central Universities (No. buctrc201910), National Natural Science Foundation of China (81602644), the project of Basic Research Cooperation of Beijing-Tianjin-Hebei (H2019104018) and the grant from the Ministry of Science and Technology of China (2010ZX09401-403). Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: Informed consents were obtained from patients and this study was approved by the Research Ethics Board at Shanghai Jiaotong University.