Urothelial carcinoma in situ (CIS) is an aggressive phenotype of non-muscle-invasive bladder cancer. Molecular features unique to CIS compared to high-grade papillary tumors are underexplored. RNA sequencing of CIS, papillary tumors, and normal urothelium showed lower immune marker expression in CIS compared to papillary tumors. We identified a 46-gene expression signature in CIS samples including selectively upregulated known druggable targets MTOR, TYK2, AXIN1, CPT1B, GAK, and PIEZO1 and selectively downregulated BRD2 and NDUFB2. High expression of selected genes was significantly associated with CIS in an independent dataset. Mutation analysis of matched CIS and papillary tumors revealed shared mutations between samples across time points and mutational heterogeneity. CCDC138 was the most frequently mutated gene in CIS. The immunological landscape showed higher levels of PD-1-positive cells in CIS lesions compared to papillary tumors. We identified CIS lesions to have distinct characteristics compared to papillary tumors potentially contributing to the aggressive phenotype.
iScience. 2024 Feb 09*** epublish ***
Meenakshi Anurag, Trine Strandgaard, Sung Han Kim, Yongchao Dou, Eva Comperat, Hikmat Al-Ahmadie, Brant A Inman, Ann Taber, Iver Nordentoft, Jørgen Bjerggaard Jensen, Lars Dyrskjøt, Seth P Lerner
Department of Medicine, Dan L. Duncan Comprehensive Cancer Center and Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA., Department of Molecular Medicine Aarhus University Hospital, 8200 Aarhus N, Denmark., Scott Department of Urology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA., Department of Pathology, Medical University Vienna, Vienna General Hospital, 1090 Wien, Austria., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Urologic Oncology, Western University, London, ON, USA., Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark.