Figure 1.

Passenger mutations serve as lineage markers, and driver mutations lead to subclones whose size is a function of strength and timing of the driver. A. Mutations (star) that arise during DNA replication will be passed on in heterozygous state to one of the daughter cells. Mutations that arise during interphase (not shown), such as incorrectly repaired DNA damage, will likely be passed on to both daughter cells. B. Mutations serve as lineage markers because they are passed on to only their progeny and are not horizontally transferred. C. Drivers initiate proliferation and then increase the growth rate, which leads to subclones (or metastases) that are marked by ever increasing numbers of mutations. When the ancestor is old, as in slowly-growing neoplasias such as columnar cell lesions in breast, the number of mutations that are shared by all cells of the neoplasia is comparatively lower than the number of mutations in a fast-growing tumor whose ancestral cell is more recent. Note that, in the primary tumor, the subclones (blue and magenta) have to grow sufficiently more quickly to be detectable compared to the already existing and still-expanding original clone (green).