The role of genomic instability in human carcinogenesis

Neoplastic cells typically possess numerous genomic lesions, which may incl ude sequence alterations (point mutations, small deletions, and insertions) and/or gross structural abnormalities in one or more chromosomes (large-sc ale deletions, rearrangements, gene amplifications). Based upon this genera l observation, it has been suggested that cancer cells are genetically unst able, and that acquisition of genomic instability may represent an early st ep in the process of carcinogenesis and a general feature of many human tum ors. Numerous studies have appeared that characterize the nature and freque ncy of occurrence of various molecular lesions in human tumors, and signifi cant progress has been made towards the elucidation of the molecular mechan isms that govern genetic stability in normal cells and genetic instability in neoplastic cells. In this review, we examine the evidence that genomic i nstability 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 th ese pathways.