The role of genomic instability in human carcinogenesis

Neoplastic cells typically possess numerous genomic lesions, which may include sequence alterations (point mutations, small deletions, and insertions) and/or gross structural abnormalities in one or more chromosomes (large-scale deletions, rearrangements, gene amplifications). Based upon this general observation, it has been suggested that cancer cells are genetically unstable, and that acquisition of genomic instability may represent an early step in the process of carcinogenesis and a general feature of many human tumors. Numerous studies have appeared that characterize the nature and frequency of occurrence of various molecular lesions in human tumors, and significant progress has been made towards the elucidation of the molecular mechanisms that govern genetic stability in normal cells and genetic instability in neoplastic cells. In this review, we examine the evidence that genomic instability plays a significant role in the genesis of various human tumors. Furthermore, we consider the possible molecular pathways to tumorigenesis in humans and how different forms of genetic instability may impact upon these pathways.