Page 304 - 20dynamics of cancer

CELL LINEAGE HISTORY 289

which heritable changes accumulate. The phylogenetic shape influences
the rate at which changes accumulate and therefore the dynamics of
cancer progression.
The principles of lineage shape and progression are clear enough, but
how can we figure out the actual history of stem cell lineages in an ep-
ithelial tissue compartment? In humans, one cannot use direct labeling
or other invasive techniques, so to study the cell lineage histories, one
must be able to read the past changes of cell lineages from the current
differences between cells. From those current differences, one can infer
how changes accumulated in the ancestral lineages that coalesce back
to the common ancestor.
To infer phylogenetic history, one must study the right kind of char-
acter. If the character changes too slowly relative to the time scale of
study, then the individual cells will not differ enough to infer historical
relations. For example, if DNA point mutations happen at about 10 −9
3
per base per cell division, then over a period of about 10 generations,
6
one expects only one change per 10 bp in each cell relative to the com-
mon ancestor. With so little change, all of the extant cells would be
6
nearly identical across sequences of up to 10 bp, and it would be im-
possible to reconstruct the history. At the other extreme, if characters
change too fast, then the traces of history disappear.
3
In a normal gastrointestinal crypt, with up to 10 or so cell genera-
tions, standard DNA point mutations happen too rarely to reconstruct
history with reasonable efficiency. To obtain sufficient information,
Yatabe et al. (2001) measured methylation patterns. Adjacent DNA nu-
cleotide sites that contain the bases C and G, linked by a phosphodiester
bond and written CpG, may exist in a methylated or unmethylated state.
Daughter cells inherit the methylation pattern of their parental cell. Ran-
dom changes in the methylation state of each CpG pair happen roughly
on the order of 10 −5 per site per cell division (Shmookler Reis and Gold-
stein 1982; Pfeifer et al. 1990), which is much more frequent than point
mutations in DNA sequence at about 10 −9 per site per cell division.

NORMAL COLON CRYPTS

No one has yet reconstructed the phylogeny of cell lineages by study
of methylation patterns. But Yatabe et al. (2001) developed a test of
alternative shapes for stem cell lineages.