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308 CHAPTER 14

that only a limited fraction of cells retain or could acquire the stem-like
properties needed for progression.

SPATIOTEMPORAL VARIATION IN PROGRESSION
Several developmental mutant patches appear in the case of inherited
glomuvenous malformations; p53 mutant patches can often be detected
in normal tissue. Those fields form large, easily studied mutant patches
on readily accessible surface tissues. Many more mutants must exist
throughout normal tissue, in the hundreds of other genes that can affect
progression.
In other words, the organism evolves continually in a mosaic way.
Patches of varying size progress to different stages on the pathway to
disease. Current data on evolving mosaicism focus on a few genes in
a few tissues, measured over broad tissue patches. Soon, technology
will allow measurement of more genes at finer spatial scales. With such
data, we will begin to infer cell lineage histories with regard to the ac-
cumulation of heritable change. The cell lineage histories provide the
ultimate explanation of somatic evolution and progression to disease.
The diseases affected by somatic evolution may go beyond cancer, to
include various syndromes that increase with age (Wallace 2005).

14.4 Summary

This chapter reviewed recent studies on the somatic evolution of
cell lineages. Because cancer arises from the accumulation of herita-
ble changes in cell lineages, such studies will play a key role in future
analyses of cancer progression. Advancing genomic technologies will
soon yield much greater resolution in the measurement of heritable cel-
lular changes. To interpret those data, we will have to understand how
such changes influence the dynamics of progression and the patterns of
age-specific incidence. Shifts in incidence curves provide the ultimate
measure of causation in cancer.