On the origin of multiple mutations in human cancers

Tumor progression is a multi-step process, proceeding by multiple alteratio ns from a normal cell to a localized tumor, and finally to one that acquire s the ability to invade and metastasize. Tumors are characterized by many m utations in the form of base substitutions, deletions, chromosomal transloc ations, and gene amplifications, and these mutations are found to accumulat e as tumors progress. In contrast, spontaneous mutations are very rare even ts. Considering the high fidelity of DNA replication in normal cells, it se ems improbable that spontaneous mutations could be the source of the large numbers of genetic alterations that are observable in cancer cells. The que stion of how multiple mutations accumulate in tumor cells is one of conside rable interest, since understanding the source of these mutations may facil itate the detection of tumors and may provide new approaches to cancer prev ention. We have proposed that the multiple mutations detectable in cancer c ells result from a mutator phenotype, in which loss of a genome stability f unction occurs early during tumor development and predisposes the tumor cel l to the accumulation of further mutations. We will first consider the evid ence that cancer cells manifest a mutator phenotype, and subsequently discu ss the possibility that a mutator phenotype cart be selected and can be tra nsient as tumors progress.