Non-Muscle-Invasive Bladder Carcinoma with Respect to Basal Versus Luminal Keratin Expression

Abstract

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.

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation

“…In a cohort of high-grade papillary NMIBCs, the CK5/6high/CK20high DP cases were enriched for PI3K-Akt signaling and connected to Lindgren's cluster 1 by Gene Set Enrichment Analysis, consisting of tumors with favorable clinical outcome [76], in keeping with other studies [33,79,80].…”

“…In the study by Jung et al, the CK5/6low/CK20low DN group was regarded as an intermediate stage between CK/6+ basal-like and CK20+ luminal-like tumors, showing a moderate expression of cell cycle progression genes, and a higher level of a protein synthetic/metabolic signature genes than luminal-like BCs [ 76 ].…”

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 1: General Issues and Marker Expression

“…Furthermore, the cohort of pure high-grade NMIBCs assessed by Schnitzler et al featured a luminal-like phenotype, along with a low FGFR3 / CDKN2A alteration frequency and a high rate of mutations in genes encoding chromatin-modifying proteins [ 75 ]. It has been suggested that such clinically aggressive luminal-like NMIBCs might be enriched for aberrations in junctional complexes, high level of copy number alteration [ 26 , 76 , 77 ], along with the cell cycle, proliferation, and progression gene sets [ 78 ].…”