Page 310 - 20dynamics of cancer

CELL LINEAGE HISTORY 295

Tsao et al. (1999) used microsatellite variability to reconstruct the
cell lineage history of colorectal cancer progression in tissue that is de-
ficient in mismatch repair. They tested two alternative scenarios for cell
lineage history between tissues sampled from adenomas and adjacent
cancerous outgrowths. Figure 14.3 shows the two alternatives.
In Figure 14.3a, the tissue progresses through repeated clonal suc-
cessions. At any time, all cells derive from the common ancestor of the
most recent clonal succession. Under this scenario, cells derived from
the adenoma and the neighboring cancerous outgrowth have a relatively
recent common ancestor.
In Figure 14.3b, clonal successions occur rarely. Instead, the tissue re-
tains multiple distinct lineages. Under this scenario, cells derived from
the adenoma and the neighboring cancerous outgrowth have a relatively
distant common ancestor.
Tsao et al. (1999) tested these alternatives by measuring relative times
as follows. Loss of mismatch repair (MMR ) initiates an increased mu-
−
tation rate that speeds cancer progression and also increases the rate of
microsatellite mutations. By comparing the microsatellites of the ade-
noma and cancer samples with other tissues, one can estimate the to-
tal accumulation of microsatellite variation since the loss of mismatch
repair. The microsatellite variation between the adenoma and cancer
samples can then be scaled relative to the total variation, providing an
estimate for the relative timing of the adenoma-cancer split compared
with the loss of mismatch repair.
Figure 14.4 shows samples from two patients. The lineage history of
each patient closely matches the hypothetical pattern of Figure 14.3b,
in which the lineages derive from a relatively distant ancestor. Those
observations support the hypothesis that colorectal cancer progression
can retain several independent lines of progression following a key ini-
tiating event, in this case, loss of mismatch repair.

14.2 Demography of Progression

Changes in the age-onset curve of cancer measure the causal effect
of carcinogenic processes. In this regard, different cell lineage histories
have significant consequences to the extent that they alter age-specific
incidence. I discuss a few examples.