Abstract 7266: Advancing insights into disease biology of non-muscle invasive bladder cancer (NMIBC) through comprehensive multi-omics analysis

Abstract Non-muscle invasive bladder cancer (NMIBC) accounts for approximately 75% of all bladder cancer cases and has high rate of recurrence and potential progression to muscle-invasive disease. Treatment strategies for NMIBC include transurethral resection of bladder tumor (TURBT) followed mainly by Bacillus Calmette-Guérin (BCG) immunotherapy or chemotherapy. Although NMIBC management has progressed, understanding its molecular basis and changes after treatment remains critical for better prognosis, patient stratification and informed treatment strategies. Here, we conducted whole exome and transcriptomic sequencing to elucidate molecular landscape and tumor microenvironment and uncover potential prognostic biomarkers associated with BCG response. Three distinct BCG response subtypes (BRS) were assessed by BCG response subtype predictor using transcriptomic sequencing data. Comparison of genomic alterations’ prevalence and transcriptomic signatures in Kyoto Encyclopedia of Genes and Genomes (KEGG) via ssGSEA (single sample Gene Set Enrichment Analysis) between high vs low/intermediate risk were evaluated. Data from 37 pre-treatment NMIBC patients were analyzed (N = 37); including patients treated with TURBT followed by BCG N = 16, and with TURBT only N= 21. Genomic profiling of 37 patients demonstrated mutation frequencies consistent with published literature, with highest prevalence observed in Telomerase Reverse Transcriptase (TERT) (78.4%), followed by Tuberous Sclerosis Complex 1 (TSC1) (64.9%) and Lysine (K)-Specific Methyltransferase (KMT)2D (51.4%). Notably, mutation frequency of Fibroblast Growth Factor Receptor 3 (FGFR3) was higher among low- and intermediate-risk groups (66.7%, N = 15) compared to high-risk groups (36.4%, N = 22). Pathway score calculated using ssGSEA from transcriptomic profiling revealed a markedly higher gene expression profile enriched in cell-cycle pathway in among high- compared to low- and intermediate-risk groups (p = 0.033). Patients with BRS3 tumors exhibited significantly reduced progression free survival (PFS) versus BRS1/2 (p= 0.0095, HR = 5.92), following BCG treatment. BRS3 tumors demonstrated elevated expression of epithelial-mesenchymal transition and basal markers and were characterized by an immunosuppressive profile. We identified that FGFR3 mutation rate is higher among low- and intermediate risk. Cell cycle dysregulation is known to contribute in tumor progression and aggressiveness of bladder cancer; our pathway analysis identified cell cycle pathway enrichment among high-risk NMIBC, which enhances our understanding of NMIBC disease biology. Our data validated BRS3 subtyping in predicting poor BCG response, demonstrating robustness of this classification approach. Further investigation is warranted to confirm these findings, considering smaller cohort in this study Citation Format: Siew Kee Low, Yoshiyuki Nagumo, Xuesong Lyu, Jiarui Zhang, Jie Zhao, Kozaburo Tanuma, Satoka Kinase, Karen Urtishak, Neil Beeharry, Shibu THOMAS, Longen Zhou, Hiroyuki Nishiyama. Advancing insights into disease biology of non-muscle invasive bladder cancer (NMIBC) through comprehensive multi-omics analysis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7266.