Non-muscle-invasive bladder cancer (NMIBC) consists of transcriptional subtypes that are distinguishable from those of muscle-invasive cancer. We aimed to identify genetic signatures of NMIBC related to basal (K5/6) and luminal (K20) keratin expression. Based on immunohistochemical staining, papillary high-grade NMIBC was classified into K5/6-only (K5/6High-K20Low), K20-only (K5/6Low-K20High), double-high (K5/6High-K20High), and double-low (K5/6Low-K20Low) groups (n = 4 per group). Differentially expressed genes identified between each group using RNA sequencing were subjected to functional enrichment analyses. A public dataset was used for validation. Machine learning algorithms were implemented to predict our samples against UROMOL subtypes. Transcriptional investigation demonstrated that the K20-only group was enriched in the cell cycle, proliferation, and progression gene sets, and this result was also observed in the public dataset. The K5/6-only group was closely regulated by basal-type gene sets and showed activated invasive or adhesive functions. The double-high group was enriched in cell cycle arrest, macromolecule biosynthesis, and FGFR3 signaling. The double-low group moderately expressed genes related to cell cycle and macromolecule biosynthesis. All K20-only group tumors were classified as UROMOL "class 2" by the machine learning algorithms. K5/6 and K20 expression levels indicate the transcriptional subtypes of NMIBC. The K5/6Low-K20High expression is a marker of high-risk NMIBC.
International journal of molecular sciences. 2020 Oct 19*** epublish ***
Minsun Jung, Insoon Jang, Kwangsoo Kim, Kyung Chul Moon
Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea., Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea., Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul 03080, Korea.