Cell Cycle Regulation of Gene Amplification

There is now overwhelming evidence that tumors typically comprise a single clone descended from a single founder cell. However, the conversion of a normal cell into a malignant cancer involves the accumulation of multiple genetic changes. This is not surprising, since cancer development minimally requires the cell to acquire an extended life span, growth factor and substratum independence, the capacity to invade and colonize new locations, and the ability to recruit a new blood supply. Studies of the age incidence of various cancers (Armitage and Doll 1954) and molecular analyses of the specific changes that occur at different stages (see, e.g., Fearon and Vogelstein 1990) indicate that at least six genetic changes typically accumulate in a multistep process referred to as tumor progression. As described below, mutations that result in genetic instability play an important role in this process.