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Bladder cancer is the most common cancer of the urinary tract with ~380,000 new cases and ~150,000 deaths per year worldwide. It ranks fifth among cancers in men in Western countries. Epidemiological studies identify a range of environmental risk factors, many of which reflect exposure to excreted carcinogenic molecules. Most bladder cancers are urothelial carcinomas. At presentation, roughly 75% of patients have non-muscle-invasive bladder cancer and 25% have muscle-invasive or metastatic disease. About 50% of non-muscle-invasive bladder cancers are low grade, whereas most muscle-invasive or metastatic tumors are high grade. Morphologically, bladder tumors can be divided into papillary, solid, and mixed types. The papillary type is predominant, especially in non-muscle-invasive bladder cancer.
Bladder tumors can be grouped based on gene expression patterns into basal and luminal subtypes, similar to the corresponding subtypes of breast cancer. Luminal muscle-invasive bladder cancers are enriched for uroplakins, KRT20, ERBB2 and differentiation markers such as fork head box A1 (FOXA1), GATA-binding protein 3 (GATA3), tripartite motif-containing protein 24 (TRIM24) and peroxisome proliferator-activated receptor‑γ (PPARγ), and these frequently have papillary morphology and FGFR3 upregulation and/or mutation. Choi et al. described a luminal subtype termed ‘p53‑like’ with an activated wild-type p53 signature, low levels of cell cycle and proliferation markers, and enrichment of myofibroblast and extracellular matrix markers, perhaps reflecting stromal and fibroblast infiltration. The infiltrated subgroup of Sjödahl et al. mostly overlapped with this p53-like subgroup. Tumors in TCGA Cluster II shared features with luminal and p53‑like subtypes, and some basal and luminal tumors described by Damrauer et al. also exhibited characteristics of the p53‑like subgroup. Tumors expressing basal markers (KRT5, KRT6, KRT14, CD44 and CDH3) were present in these studies. Besides, the SCCL (or basal) muscle-invasive bladder cancers showed the worst prognosis, and those with papillary architecture and high expression levels of FGFR3, E‑cadherin, GATA3, FOXA1 and uroplakins had the best prognosis. Bioinformatics analyses implicated transcription factors that are active in the basal or stem cell compartment of the normal urothelium — signal transducer and activator of transcription 3 (STAT3), nuclear factor‑κΒ (NF‑κB), hypoxia-inducible factor 1 (HIF1) and p63 — as potential regulators in basal tumors, and PPARγ and oestrogen receptor pathways were implicated in luminal tumors.
Chemosensitive basal bladder cancers seem to be enriched with an immune signature, and although some data suggest that basal tumors might be sensitive to immune checkpoint blockade, other data suggest that although basal tumors have the highest level of programmed death ligand 1 (PD-L1)-enriched T cells, their rate of response to anti-PD-L1 therapies is lower than that of luminal cluster-II tumors. Basal bladder cancers are also enriched with epidermal growth factor receptor (EGFR) and hypoxia-inducible factor 1. Preclinical data confirmed that basal tumors are sensitive to EGFR inhibitors, and patients with basal tumors responded better than patients with luminal tumors to combination treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) plus bevacizumab, which inhibits the hypoxia-inducible factor 1 target vascular endothelial growth factor (VEGF). Luminal bladder cancers, in addition to being enriched with activating FGFR3 mutations, are enriched with activating ERBB2 and ERBB3 mutations, which support the clinical assessment of FGFR-targeting and ERBB-targeting drugs in patients with luminal tumors.
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