Figure 1. Mutational cascade during carcinogenesis as envisioned by the mutator hypothesis.

During tumor progression there is a progressive increase in mutations resulting from unrepaired DNA damage. Most have no effect on cellular phenotypes (neutral), others enhance proliferation (drivers), and others cause increased mutagenesis (mutators). As the tumor encounters environmental restrictions such as reduced nutrition, inadequate angiogenesis, hypoxia, etc. specific mutations are selected. Circles represent mutations in genes that enhance mutagenesis, triangles indicate mutations selected that enhance proliferation under adverse conditions, and white rectangles represent passenger mutations of unknown functions. Note that many of the tumor cells contain multiple drivers and mutators. Also to be noted is that many topographically distinct mutations are maintained during tumor proliferation. Adapted from [22].