Identification of Differential Tumor Subtypes of T1 Bladder Cancer.

Stage T1 bladder cancers have the highest progression and recurrence rates of all non-muscle-invasive bladder cancers (NMIBCs). Most T1 cancers are treated with bacillus Calmette-Guérin (BCG), but many will progress or recur, and some T1 patients will die from bladder cancer.

Particularly aggressive tumors could be treated with early cystectomy. To better understand the molecular heterogeneity of T1 cancers, we performed transcriptome profiling and unsupervised clustering, and identified five consensus subtypes of T1 tumors treated with repeat transurethral resection and induction and maintenance BCG. The T1-LumGU subtype was associated with carcinoma in situ (CIS; six/13, 46% of all CIS), had high E2F1 and EZH2 expression, and was enriched in E2F target and G2M checkpoint hallmarks. The T1-Inflam subtype was inflamed and infiltrated with immune cells. While most T1 tumors were classified as luminal papillary, the T1-TLum subtype had the highest median luminal papillary score and FGFR3 expression, no recurrence events, and the fewest copy number gains. T1-Myc and T1-Early subtypes had the most recurrences (14/30 within 24 mo), the highest median MYC expression, and, when combined, had significantly worse recurrence-free survival than the other three subtypes. T1-Early had five (38%) recurrences within the first 6 mo of BCG, and repressed IFN-α and IFN-γ hallmarks and inflammation. We developed a single-patient T1 classifier and validated our subtype biology in a second cohort of T1 tumors. Future research will be necessary to validate the proposed T1 subtypes and to determine if therapies can be individualized for each subtype. PATIENT SUMMARY: We identified and characterized expression subtypes of high-grade stage T1 bladder cancer that are biologically heterogeneous and have variable responses to bacillus Calmette-Guérin treatment. We validated the subtypes and describe a single-patient classifier.

European urology. 2020 Jul 16 [Epub ahead of print]

A Gordon Robertson, Clarice S Groeneveld, Brian Jordan, Xiquo Lin, Kimberly A McLaughlin, Arighno Das, Leigh Ann Fall, Damiano Fantini, Timothy J Taxter, Lauren S Mogil, Sia Viborg Lindskrog, Lars Dyrskjøt, David J McConkey, Robert S Svatek, Aurélien de Reyniès, Mauro A A Castro, Joshua J Meeks

Dxige Research Inc., Courtenay, BC, Canada., Cartes d'Identité des Tumeurs Program, Ligue Nationale Contre le Cancer, Paris, France; Oncologie Moleculaire, Institut Curie, Equipe Labellisée Ligue Contre le Cancer, Paris, France., Department of Urology, University of Washington, Seattle, WA, USA., Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Departments of Urology, Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Tempus Labs, Inc., Chicago, IL, USA., Center for Translational Data Science, University of Chicago, Chicago, IL, USA., Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Johns Hopkins Greenberg Bladder Cancer Institute, Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA., Experimental Developmental Therapeutics Program, UT Health MD Anderson, San Antonio, TX, USA; Department of Urology, UT Health San Antonio, San Antonio, TX, USA., Cartes d'Identité des Tumeurs Program, Ligue Nationale Contre le Cancer, Paris, France., Bioinformatics and Systems Biology Laboratory, Federal University of Paraná, Curitiba, Brazil., Departments of Urology, Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA. Electronic address: .

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