PO.MCB08.05 · 分子与细胞生物学
Advancing insights into disease biology of non-muscle invasive bladder cancer (NMIBC) through comprehensive multi-omics analysis
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摘要 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
利益披露 Disclosure
S. Low,
Johnson & Johnson Employment, Are employee of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson.
Y. Nagumo,
Astellas ).
Chugai Pharma ).
Johnson & Johnson ).
AstraZeneca Other, consulting fees.
Merck Sharp & Dohme Other, consulting fees.
Ono Pharmaceutical consulting fees.
AstraZeneca Other, honoraria for speakers’ bureaus.
Astellas honoraria for speakers’ bureaus.
Bristol Myers Squibb honoraria for speakers’ bureaus.
Merck Biopharma Co. Ltd., honoraria for speakers’ bureaus.
Merck Sharp & Dohme honoraria for speakers’ bureaus.
Nippon Kayaku Co. Ltd honoraria for speakers’ bureaus.
Ono Pharmaceutical honoraria for speakers’ bureaus.
Pfizer honoraria for speakers’ bureaus.
X. Lyu,
Johnson & Johnson Employment, Are employee of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson.
J. Zhang,
Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson.
J. Zhao,
Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson.
K. Tanuma,
Astellas ).
Chugai Pharma ).
Johnson & Johnson ).
AstraZeneca consulting fees.
Johnson & Johnson consulting fees.
Merck Sharp & Dohme consulting fees.
Ono Pharmaceutical consulting fees.
AstraZeneca honoraria for speakers’ bureaus.
Astellas honoraria for speakers’ bureaus.
Bristol Myers Squibb honoraria for speakers’ bureaus.
Merck Biopharma Co. Ltd honoraria for speakers’ bureaus.
Merck Sharp & Dohme honoraria for speakers’ bureaus.
Nippon Kayaku Co. Ltd honoraria for speakers’ bureaus.
Ono Pharmaceutical honoraria for speakers’ bureaus.
Pfizer honoraria for speakers’ bureaus.
S. Kinase,
Astellas ).
Chugai Pharma ).
Johnson & Johnson ).
AstraZeneca consulting fees.
Johnson & Johnson consulting fees.
Merck Sharp & Dohme consulting fees.
Ono Pharmaceutical consulting fees.
AstraZeneca honoraria for speakers’ bureaus.
Astellas honoraria for speakers’ bureaus.
Bristol Myers Squibb honoraria for speakers’ bureaus.
Merck Biopharma Co. Ltd honoraria for speakers’ bureaus.
Merck Sharp & Dohme honoraria for speakers’ bureaus.
Nippon Kayaku Co. Ltd honoraria for speakers’ bureaus.
Ono Pharmaceutical honoraria for speakers’ bureaus.
Pfizer honoraria for speakers’ bureaus.
K. Urtishak,
Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson.
N. Beeharry,
Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson.
S. Thomas,
Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson.
L. Zhou,
Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson.
H. Nishiyama,
Astellas ).
Chugai Pharma ).
Johnson & Johnson ).
AstraZeneca consulting fees.
Johnson & Johnson consulting fees.
Merck Sharp & Dohme consulting fees.
Ono Pharmaceutical consulting fees.
AstraZeneca honoraria for speakers’ bureaus.
Astellas honoraria for speakers’ bureaus.
Bristol Myers Squibb honoraria for speakers’ bureaus.
Merck Biopharma Co. Ltd honoraria for speakers’ bureaus.
Merck Sharp & Dohme honoraria for speakers’ bureaus.
Nippon Kayaku Co. Ltd honoraria for speakers’ bureaus.
Ono Pharmaceutical honoraria for speakers’ bureaus.
Pfizer honoraria for speakers’ bureaus.