Multiple steps in carcinogenesis involving alterations of multiple tumor suppressor genes.

Recent advances in molecular genetics have made it possible to understand the molecular mechanisms of human cancer progression. The results indicate that clinically evident tumor cells already carry multiple genetic alterations and further accumulation of genetic alteration occurs during tumor progression. It is widely accepted that tumor suppressor genes play a central role in the genesis and progression of human cancers, as frequent alterations of tumor suppressor genes have been found in a variety of human cancers. Molecular analyses of various stages of human cancers, from precancerous lesions to advanced or metastatic tumors, indicate that sequential accumulation of genetic alterations correlates with more malignant phenotypes of tumor cells. Furthermore, biological studies of tumor suppressor genes have revealed that a single gene defect is not sufficient for the cells to gain growth advantage and start clonal expansion in vivo. These results are consistent with the concept of human multistage carcinogenesis, indicated by experimental animal models and epidemiological studies. Although it is supposed that there are more than 20 tumor suppressor genes in the human genome, only a few tumor suppressor genes have been identified to date. Thus, further studies should focus on the identification and characterization of novel tumor suppressor genes, and molecular analysis of those genes in human cancer would be of great help in clarifying the multiple steps in the process of human carcinogenesis.