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CELL LINEAGE HISTORY 303

course of progression (Figure 14.4). Those observation are consistent
with multilineage progression rather than frequent clonal succession.
Maley et al. (2006) provide further support for the association between
genetic diversity in precancerous lesions and progression. They stud-
ied Barrett’s esophagus, a premalignant lesion that often covers several
centimeters of tissue and is too large for complete removal. Multiple
biopsies provided several tissue samples per individual.
Maley et al. (2006) measured a variety of morphological and genetic
attributes from each patient. Greater size of the premalignant lesion
provided a weak but significant predictor for the risk of progression to
malignancy. Indicators of genetic instability—loss of heterozygosity at
p53 and ploidy abnormalities—provided strong predictors for the risk
of progression.
Genetic diversity within a lesion also provided a strong predictor of
progression. At least two different hypotheses may explain why some
lesions have more genetic diversity than others. First, mutations happen
more often in some lesions than in others. Second, lineages may trace
back to more distant ancestors in some lesions than others, allowing
more time for diversity to accumulate.
To test whether progression depended only on mutation rate rather
than lineage depth, Maley et al. (2006) calculated the effect of genetic
diversity while controlling for indicators of genetic instability and mu-
tation rate. They found that genetic diversity had a strong effect in-
dependently of indicators of mutation rate, suggesting that diversity
caused by deep lineages correlates with progression.
From these observations on Barrett’s esophagus, Maley et al. (2006)
and Shibata (2006) conclude that the maintenance of multiple indepen-
dent lineages accelerates progression. It may be that each clonal succes-
sion drives out genetic variability in a tissue, reducing the opportunity
for future mutations to create combinations of genes that promote car-
cinogenesis.
All of these examples provide only indirect support for multilineage
progression; they certainly do not rule out the importance of clonal ex-
pansion in progression. But remember that we are just in the very first
years during which technology allows direct measurement of genetic
variation in samples of tissues. Advances in technology will eventually
provide better reconstructions of cell lineage history (e.g., Backvall et al.