ALTERATIONS OF TUMOR-SUPPRESSOR GENES IN BLADDER-CANCER

The etiopathogenesis of neoplastic diseases is characterized by its mu ltiple nature. Multiple biological and physical agents have been ident ified as initiating or promoting neoplastic mechanisms. However, they all appear to have common molecular basis, granting genetic instabilit y and causing somatic derangements to preneoplastic and tumor cells. T arget genes implicated in cellular transformation and tumor progressio n have been divided into two categories: proto-oncogenes (that when ac tivated become dominant events characterized by gain of function) and tumor suppressor genes (recessive events characterized by the loss of function). Alterations in proto-oncogenes and tumor suppressor genes s eem equally prevalent among human cancers. Multiple mutations appear t o be required to conform the malignant phenotype. It is, therefore, co nceivable to view cancer as fundamentally a genetic disease entailing inherited (also called ''germline'') or acquired (also termed ''somati c'') mutations of genes in these two categories. The concept of tumor suppressor genes was established in studies with somatic cell hybrids, revealing that when malignant cells were fused with normal cells some of the hybrids were nontumorigenic. Clinically, the existence and rel evance of this category of genes was based on epidemiological studies of the intraocular childhood tumor retinoblastoma, and it was postulat ed that two independent events were needed to inactivate a given gene. It was further shown that, in general, that was achieved by an alleli c loss followed by a point mutation of the remaining allele. A family of genes has been characterized that follows this ''two-hit'' model in cluding the two prototype suppressors genes: the retinoblastoma (RB) a nd the TP53 (also known as p53) genes. These genes encode a variety of molecules with distinct biological properties, including cell cycle r egulation and cellular differentiation. Germline and somatic mutations of these genes appear to be the most common abnormalities found in hu man cancer including bladder neoplasms. More recent studies have shown that inactivation of some of these genes (ie, TP53) occurs in bladder tumors that have a more aggressive clinical outcome and poor prognosi s. In the following subheadings, the authors have reviewed the molecul ar abnormalities associated with these recessive genes in bladder tumo rs and discuss the potential clinical use of their detection. The impl ementation of objective predictive assays to identify these alteration s in clinical material will enhance the ability to assess tumor biolog ical activities and to design effective treatment regimens. The need n ow is to translate this newly developed scientific knowledge into diag nostic and therapeutic strategies, which, in turn, will enhance qualit y of life and prolong patient survival. Copyright (C) 1997 by W.B. Sau nders Company.