Figure 1.

Two distinct molecular pathways for the initiation and progression of urothelial carcinoma. Normal urothelium acquire both aberrant DNA hypermethylation and hypomethylation, prior to the onset of genetic mutations. Normal-appearing urothelium then can transform into either noninvasive (Ta/T1) tumors or invasive tumors (T2–T4) through the accumulation of activating mutations of FGFR3 (fibroblast growth factor receptor 3) or TP53, respectively. Approximately, 80% of all newly diagnosed cases are noninvasive papillary tumors, which do not often progress to invasive tumors. Acquiring subsequently TP53 mutation is necessary for the progression. Noninvasive tumors acquire less hypermethylation and more aberrant hypomethylation, among which a group of genes is distinctively hypomethylated in noninvasive tumors. Invasive tumors display the reversed methylation profile.