Loss of <scp> <i>METTL3</i> m6A </scp> methyltransferase results in short‐term progression and poor treatment outcome of bladder cancer patients

Bladder cancer (BlCa) exhibits a highly heterogeneous molecular landscape and treatment response, underlining the pressing need for personalized prognosis. N6-methyladenosine (m6A) constitutes the most abundant RNA modification, modulates RNA biology/metabolism, and maintains cellular homeostasis, with its dysregulation involved in cancer initiation and progression. Herein, we evaluated the clinical value of METTL3 m6A methyltransferase, the main catalytic component of m6A methylation machinery, in improving BlCa patients' risk stratification and prognosis. The screening cohort of the study included 213 patients. The UROMOL (n = 535) was analyzed as a validation cohort for non-muscle-invasive BlCa (NMIBC), while the TCGA-BLCA (n = 412) and Mariathasan et al. (n = 348) cohorts were analyzed for muscle-invasive BlCa (MIBC). Disease recurrence/progression and patients' mortality were assessed as clinical endpoints for NMIBC and MIBC, respectively. Internal validation of Cox regression models was conducted using bootstrap analysis, while the clinical utility for patient prognosis was evaluated through decision curve analysis. Reduced METTL3 expression was correlated with muscle-invasive disease and tumors of advanced stage. Loss of METTL3 expression at diagnosis was strongly associated with higher risk of short-term progression (HR = 2.903, 95% CI: 1.303-6.464, p = 0.006) to invasive stages in NMIBC and with worse survival of MIBC patients (HR = 1.908, 95% CI: 1.020-3.567, p = 0.042). Consistently, validation cohorts confirmed the poor treatment outcomes in patients exhibiting loss of METTL3. Finally, METTL3-fitted multivariate models improved risk stratification and offered superior clinical benefit for NMIBC and MIBC prognostication compared to clinically established disease markers. Overall, loss of METTL3 expression correlates with inferior treatment outcomes in BlCa, driving more accurate risk stratification and ameliorating patients' prognosis in BlCa.