Page 306 - 20dynamics of cancer

CELL LINEAGE HISTORY 291

by symmetric division of another stem lineage to produce two daughter
stem cells.
Suppose purely asymmetric division occurs, and all independent stem
lineages remain over time (Figure 14.1a). Then two lineages within a
crypt will on average be as different as a pair of lineages sampled from
different crypts. In each case, every lineage traces back to a different
ancestral stem cell that seeded the colon crypts at the end of develop-
ment.
Alternatively, suppose that occasional clonal succession occurs with-
in crypts (Figure 14.1b). Then two lineages within a crypt will on average
be more similar to each other than a pair of lineages sampled from dif-
ferent crypts. Within crypts, the current cells trace back to a recent com-
mon ancestor at the time of the last clonal succession. Between crypts,
cells trace back to a more distant common ancestor that preceded the
separation of the ancestral stem cells at the end of development.
Yatabe et al. (2001) showed that less variation in methylation occurs
within crypts than between crypts, supporting the clonal succession
model (Kim and Shibata 2002). Full evaluation of the data requires var-
ious assumptions about the number of stem cells per crypt, the rate
of cell division, and the accuracy of the methylation measurement pro-
cedure (Ro and Rannala 2001). The overall conclusion of clonal suc-
cession appears to be well supported, but the estimated rate for clonal
successions depends on several assumptions in the quantitative analy-
sis. Based on those assumptions, Yatabe et al. (2001) infer that clonal
succession happens on average about every 8.2 years.

COLON CRYPTS WITH AN INHERITED APC MUTATION
Inherited mutations to the APC locus cause familial adenomatous
polyposis (FAP). In FAP, individuals may develop thousands of indepen-
dently transformed crypts that lead to polyps or more aggressive tumors
(Kinzler and Vogelstein 2002).
Mutations to APC play a role in stem cell dynamics (Kinzler and Vo-
gelstein 2002). So Kim et al. (2004) hypothesized that those individuals
who inherit an APC mutation may have altered patterns of stem lineage
evolution in crypts when compared to normal individuals. To test this
hypothesis, they compared the diversity of methylation patterns within
crypts. Those crypts that carry germline APC mutations had higher
methylation diversity than did crypts from normal individuals.