Alterations of tumor suppressor genes in bladder cancer.

The etiopathogenesis of neoplastic diseases is characterized by its multiple nature. Multiple biological and physical agents have been identified as initiating or promoting neoplastic mechanisms. However, they all appear to have common molecular basis, granting genetic instability and causing somatic derangements to preneoplastic and tumor cells. Target genes implicated in cellular transformation and tumor progression have been divided into two categories: proto-oncogenes (that when activated become dominant events characterized by gain of function) and tumor suppressor genes (recessive events characterized by the loss of function). Alteration in proto-oncogenes and tumor suppressor genes seem equally prevalent among human cancers. Multiple mutations appear to be required to conform the malignant phenotype. It is, therefore, conceivable to view cancer as fundamentally a genetic disease entailing inherited (also called "germline") or acquired (also termed "somatic") 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 relevance of this category of genes was based on epidemiological studies of the intraocular childhood tumor retinoblastoma, and it was postulated that two independent events were needed to inactivate a given gene. It was further shown that, in general, that was achieved by an allelic loss followed by a point mutation of the remaining allele. A family of genes has been characterized that follows this "two-hit" model including the two prototype suppressors genes: the retinoblastoma (RB) and the TP53 (also known as p53) genes. These genes encode a variety of molecules with distinct biological properties, including cell cycle regulation and cellular differentiation. Germline and somatic mutations of these genes appear to be the most common abnormalities found in human cancer including bladder neoplasms. More recent studies have shown that inactivation of some of these genes (i.e., TP53) occurs in bladder tumors that have a more aggressive clinical outcome and poor prognosis. In the following subheadings, the authors have reviewed the molecular abnormalities associated with these recessive genes in bladder tumors and discuss the potential clinical use of their detection. The implementation of objective predictive assays to identify these alterations in clinical material will enhance the ability to assess tumor biological activities and to design effective treatment regimens. The need now is to translate this newly developed scientific knowledge into diagnostic and therapeutic strategies, which, in turn, will enhance quality of life and prolong patient survival.