On the origin of multiple mutations in human cancers

Tumor progression is a multi-step process, proceeding by multiple alterations from a normal cell to a localized tumor, and finally to one that acquires the ability to invade and metastasize. Tumors are characterized by many mutations in the form of base substitutions, deletions, chromosomal translocations, and gene amplifications, and these mutations are found to accumulate as tumors progress. In contrast, spontaneous mutations are very rare events. Considering the high fidelity of DNA replication in normal cells, it seems improbable that spontaneous mutations could be the source of the large numbers of genetic alterations that are observable in cancer cells. The question of how multiple mutations accumulate in tumor cells is one of considerable interest, since understanding the source of these mutations may facilitate the detection of tumors and may provide new approaches to cancer prevention. We have proposed that the multiple mutations detectable in cancer cells result from a mutator phenotype, in which loss of a genome stability function occurs early during tumor development and predisposes the tumor cell to the accumulation of further mutations. We will first consider the evidence that cancer cells manifest a mutator phenotype, and subsequently discuss the possibility that a mutator phenotype cart be selected and can be transient as tumors progress.