Perspectivesin CancerResearch Mutator Phenotype May Be Required for Multistage Carcinogenesis1

There is increasing evidence that the pathogenesis of cancer proceeds by sequential steps from normal cells to premalignant foci to localized tumors to invasive tumors and to metastatic lesions. The concept of stages of tumor progression was initially analyzed by Foulds (1), and a model for tumor progression based on genetic instability and clonal selection has been pro posed by Nowell (2). Individual steps in tumor progression have been operationally delineated in mouse skin by the responses of cells to different chemicals (3). A progression of phenotypic changes has been described in human tumors, the anatomical localization of which has made it feasible to obtain serial biopsies (2, 4). Sequential somatic chromosomal abnormalities have been reported in human cancers including malignant mel anoma (5), colon cancer (6), gliomas (7), adenocarcinoma of the esophagus (8), and small cell carcinomas of the lung (9). In addition, a multiplicity of different mutations has been carefully documented in human breast cancer (10). The dilemma is that there are too many mutations in human tumors. In this perspective, I will consider the relationships between mutation rates and cancer. At least two mutations are required to account for the chromosomal changes observed in certain human inherited diseases (11). An analysis of the literature indicates that the spontaneous mutation rate in cells is of sufficient magnitude to account for a two mutation hypothesis for the initiation of cancer. However, a larger number of mu tations are observed in many human tumors. The spontaneous mutation rate in somatic cells is not sufficient to account for these multiple mutations. If the multiple mutations in tumors are causally associated with and not just an accompaniment of cancer, then I argue that an early step in tumor progression is one that induces a mutator phenotype. An increased mutation rate in tumors could be the basis for the multiple mutations that characterize many cancers.