Genetic alterations and biological pathways in human bladder cancer pathogenesis.
Human bladder cancers are heterogeneous. For example, at first presentation papillary transitional cell carcinomas (TCCs) are typically superficial and often multifocal. Papillary TCCs frequently recur, but most never progress to invasive TCC. In contrast, bladder carcinoma in situ (CIS) usually presents as a solitary flat lesion and, if left untreated, invariably progresses to invasive TCC. Some TCC are already invasive at the time of presentation. Squamous cell carcinoma (SCC) tends to present at a later stage than most TCCs and has a relatively aggressive clinical course. Multiple genetic alterations have been identified in invasive human bladder cancers and are present in different combinations and in different frequencies in the different manifestations of bladder cancer described above. A high percentage ( approximately 67%) of superficial papillary TCCs show early losses involving chromosome 9q, while very few show either a TP53 or a CDKN2/16 mutation. Thus, loss of 9q may be the earliest event in initiation of papillary TCC. In contrast, bladder CIS and SCC show relatively low percentages of 9q loss. However, approximately 65% of bladder CIS contain a TP53 alteration and approximately 67% of bladder SCC contain a CDKN2/p16 alteration. Mutations in these two tumor suppressor genes have powerful implications for loss of genome stability and cell growth regulation, respectively, consistent with the aggressive phenotypes of these cancers. Thus, these data suggest a model of bladder cancer pathogenesis in which the predominant genetic alteration may be the "initiating event" in cancer pathogenesis and may play a role in determining the biological potential of the tumor.