MULTIPLE MUTATIONS IN HUMAN CANCERS

Increasing evidence indicates that most human cancers contain multiple mutations. The exact number of mutations, their origin, and types rem ain to be determined. An over-riding question is whether the multiple mutations that accumulate in cancers is rate-limiting for the carcinog enic process. In this review we consider the argument that the large n umbers of mutations routinely reported in human cancers cannot be acco unted for by the rate of spontaneous mutation observed in normal human cells. We will analyze different mechanisms that might account for th e accumulation of mutations in cancer cells. We conclude that cancer c ells are genetically unstable; i.e., they exhibit a mutator phenotype. The recent reports of microsatellite instability in a variety of huma n cancers have provided the first strong evidence for the presence of a mutator phenotype in human cancers. However, we still lack informati on about the relationship between microsatellite instability and mutat ions that allow cancer cells to proliferate, invade, and metastasize.