The Role of Genomic Instability in the Development of Human Cancer

Abstract

Cancer development is a multi-step process through which cells acquire increasingly abnormal proliferative and invasive behaviors. Furthermore, cancer represents a unique form of genetic disease, characterized by the accumulation of multiple somatic mutations in a population of cells undergoing neoplastic transformation (1–5). Several forms of molecular alteration have been described in human cancers, including gene amplifications, deletions, insertions, rearrangements, and point mutations (5, 6). In many cases specific genetic lesions have been identified that are associated with the process of neoplastic transformation and/or tumor progression in a particular tissue or cell type (4). Statistical analyses of age-specific mortality rates for different forms of human cancer predict that multiple (three to eight) mutations in specific target genes are required for the genesis and outgrowth of most clinically diagnosable tumors (7). In accordance with this prediction, it has been suggested that tumors grow through a process of clonal expansion driven by mutation (1,2,8–10). In this model, the first mutation leads to limited expansion of progeny of a single cell, and each subsequent mutation gives rise to a new clonal outgrowth with greater proliferative potential. The idea that carcinogenesis is a multi-step process is supported by morphologic observations of the transitions between premalignant (benign) cell growths and malignant tumors. In some tumor systems (such as colon), the transition from benign to malignant can be easily documented and occurs in discernible stages, including benign adenoma, carcinoma in situ, invasive carcinoma, and eventually local and distant metastasis (11,12). Moreover, specific genetic alterations have been shown to correlate with each of these well-defined histopathologic stages of tumor development and progression (13,14). However, it is important to recognize that it is the accumulation of multiple genetic alterations in affected cells, and not necessarily the order in which these changes accumulate, that determines tumor formation and progression. These observations suggest strongly that the molecular alterations observed in human cancers represent integral (necessary) components of the process of neoplastic transformation and tumor progression.