Genetic and molecular markers of urothelial premalignancy and malignancy

The molecular genetic changes reported in bladder tumors can be classified as primary and secondary aberrations. Primary molecular alterations may be defined as those directly related to the genesis of cancer. These are frequ ently found as the sole abnormality and are often associated with particula r tumors. Then are characteristic primary abnormalities involved in the pro duction of low-grade/well- differentiated neoplasms, which destabilize cell ular proliferation but have little effect on cellular "social" interactions or differentiation, as well as the rate of cell death or apoptosis. Other molecular events lead to high-grade neoplasms which disrupt growth control, including the cell cycle and apoptosis, and which have a major impact on b iological behavior. A primary target leading to low-grade papillary superfi cial bladder tumors resides on chromosome 9, while p53 gene alterations are commonly seen in flat carcinoma in situ. Other molecular alterations must be elucidated, as many non-invasive neoplasms have neither chromosome 9 nor p53 alterations. Novel approaches utilizing tissue microdissection techniq ues and molecular genetic assays are needed to shed further Light on this s ubject. Secondary genetic or epigenetic abnormalities may be fortuitous, or may determine the biological behavior of the tumor. Multiple molecular abnormalities are identified in most human cancers studi ed, including bladder neoplasms. The accumulation, rather than the order, o f these genetic alterations may be the critical factor that grants synergis tic activity. In this regard, it is noteworthy that many of the genes that are altered act upon the two recognized critical growth and senescence path ways, TP53 and RE. These particular molecular aberrations may be especially important to evaluate for their use in the management of bladder cancer be cause of their commonality in progressive forms of the disease. Thus, clini cal trials are underway to explore their use in specific situations, partic ularly in the surgical management of locally advanced disease, and to deter mine whether adjuvant chemotherapy in such patients may be of benefit. The use of molecular alterations in the management of non-invasive bladder neop lasms remains to be firmly established. Our knowledge of molecular alterati ons important in bladder cancer progression is far from complete, and furth er study is necessary to further elucidate crucial pathways involved in pro gression and therapeutic response. As per preneoplastic conditions, difficulties in identifying and interpreti ng the significance of phenotypic changes have imposed certain Limitations, as has an evolving nomenclature and issues of reproducibility in interpret ing morphological criteria. Nevertheless, molecular alterations involving c hromosome 9q and the INK4A locus in papillary superficial tumors vs changes in chromosomes 14q and 8q, p53 and RE in flat carcinoma in situ lesions ma y indicate a molecular basis for early events that lead to varying pathways in urothelial tumorigenesis. Studies aimed at revealing the clinical relev ance of genetic instability, as well as molecular or epigenetic alterations , in urothelium and preneoplastic lesions of otherwise morphologically norm al appearance are needed to further advance knowledge in the field. Clinical advances in bladder cancer will be facilitated by novel animal mod els paralleling the human disease. Molecular diagnostics, particularly spec ific antigen expression, fluorescence in situ hybridization and microsatell ite analyses, have shown great promise as screening and follow-up methodolo gies, and may supplement urine cytology in the diagnosis and characterizati on of new and recurrent disease. In addition, the use of high-throughput ge nomic/proteomic assays, linked to comprehensive databases, and coupled with robust bioinformatics will be key elements in elucidating the components o f regulatory and signaling pathways involved in bladder tumorigenesis and c ancer progression.