Multiomics profiling of urothelial carcinoma in situ reveals CIS-specific gene signature and immune characteristics
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
Affiliations
Meenakshi Anurag
Department of Medicine, Dan L. Duncan Comprehensive Cancer Center and Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
Trine Strandgaard
Department of Molecular Medicine Aarhus University Hospital, 8200 Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
Sung Han Kim
Scott Department of Urology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Urology, Urological Cancer Center, National Cancer Center, Goayng, Gyeonggi, Rep. Korea
Yongchao Dou
Department of Medicine, Dan L. Duncan Comprehensive Cancer Center and Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA
Eva Comperat
Department of Pathology, Medical University Vienna, Vienna General Hospital, 1090 Wien, Austria
Hikmat Al-Ahmadie
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Brant A. Inman
Department of Urologic Oncology, Western University, London, ON, USA
Ann Taber
Department of Molecular Medicine Aarhus University Hospital, 8200 Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
Iver Nordentoft
Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark
Jørgen Bjerggaard Jensen
Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark; Department of Urology, Aarhus University Hospital, Aarhus, Denmark
Lars Dyrskjøt
Department of Molecular Medicine Aarhus University Hospital, 8200 Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, 8000 Aarhus C, Denmark; Corresponding author
Seth P. Lerner
Scott Department of Urology, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Corresponding author
Summary: 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.
