Development and validation of a novel stem cell subtype for bladder cancer based on stem genomic profiling

BACKGROUND: Bladder cancer (BLCA) is the fifth most common type of cancer worldwide, with high recurrence and progression rates. Although considerable progress has been made in the treatment of BLCA through accurate typing of molecular characteristics, little is known regarding the various genetic and epigenetic changes that have evolved in stem and progenitor cells. To address this issue, we have developed a novel stem cell typing method. METHODS: Based on six published genomic datasets, we used 26 stem cell gene sets to classify each dataset. Unsupervised and supervised machine learning methods were used to perform the classification. RESULTS: We classified BLCA into three subtypes—high stem cell enrichment (SCE_H), medium stem cell enrichment (SCE_M), and low stem cell enrichment (SCE_L)—based on multiple cross-platform datasets. The stability and reliability of the classification were verified. Compared with the other subtypes, SCE_H had the highest degree of cancer stem cell concentration, highest level of immune cell infiltration, and highest sensitivity not only to predicted anti-PD-1 immunosuppressive therapy but also to conventional chemotherapeutic agents such as cisplatin, sunitinib, and vinblastine; however, this group had the worst prognosis. Comparison of gene set enrichment analysis results for pathway enrichment of various subtypes reveals that the SCE_H subtype activates the important pathways regulating cancer occurrence, development, and even poor prognosis, including epithelial-mesenchymal transition, hypoxia, angiogenesis, KRAS signal upregulation, interleukin 6-mediated JAK-STAT signaling pathway, and inflammatory response. Two identified pairs of transcription factors, GRHL2 and GATA6 and IRF5 and GATA3, possibly have opposite regulatory effects on SCE_H and SCE_L, respectively. CONCLUSIONS: The identification of BLCA subtypes based on cancer stem cell gene sets revealed the complex mechanism of carcinogenesis of BLCA and provides a new direction for the diagnosis and treatment of BLCA.