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CELL LINEAGE HISTORY 287

frequency of methylated DNA indicates the number of mitoses—a mea-
sure of mitotic age. I summarize data on the patterns of methylation
with age in different tissues and discuss how those measures of mitotic
age correspond to incidence patterns.
Another study tested the theory that progression develops through
a series of clonal successions. Direct measurement of precancerous
esophageal lesions found that progression to cancer increased with ge-
netic diversity in the lesion. Greater genetic diversity may indicate a
longer time since a common cellular ancestor and therefore less frequent
clonal succession, contradicting the theory that clonal successions play
a key role in progression.
The third section turns to measurements of somatic mosaicism, in
which patches of cells carry an inherited change from a common an-
cestor. Mosaic patches may arise by a mutation during development
or by a mutation in the adult that spreads by clonal expansion. Mosaic
patches form a field with an increased risk of progression, in which mul-
tiple independent tumors may develop. At present, the best studies of
mosaicism come from variants that cause visible skin defects, allowing
direct observation of the altered tissue.
Genomic technologies can measure heritable changes in cells that lack
an observable phenotype. Such genomic studies have already uncovered
mosaicism in numerous tissues. Advancing technology will soon allow
much more refined measures of genetic and epigenetic variation. Those
measures will provide a window onto cell lineage history with regard
to the accumulation of heritable change—the ultimate explanation of
somatic evolution and progression to disease.

14.1 Reconstructing Cellular Phylogeny

Cell lineage histories affect the accumulation of heritable changes and
the rate of carcinogenesis. For example, an expanding cell lineage poses
significant risks, because a mutation carries forward to a growing clone
of descendants. By contrast, the linear cellular history of renewal in
an epithelial compartment poses lower risk, because a mutation carries
forward only to the limited number of descendants in that single com-
partment.