Multiomics profiling of urothelial carcinoma in situ reveals CIS-specific gene signature and immune characteristics

Abstract

Urothelial carcinoma <i>in situ</i> (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 <i>MTOR</i>, <i>TYK2</i>, <i>AXIN1</i>, <i>CPT1B</i>, <i>GAK</i>, and <i>PIEZO1</i> and selectively downregulated <i>BRD2</i> and <i>NDUFB2</i>. 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. <i>CCDC138</i> 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.