Page 303 - 20dynamics of cancer

288 CHAPTER 14

One might think of this theory of cell lineages as a forward analysis:
As time moves ahead, the pattern of descent influences the accumula-
tion of heritable change and the progress of cancer.
In empirical studies, we often must consider the reverse: Given a set
of cells that carry various heritable changes, how can we infer the ances-
tral lineage history of those cells? We know that, in an organism with
a single-celled zygote, any two cells trace back to a common ancestral
cell that is either the zygote or a descendant of the zygote. Similarly,
any heritable change shared by a pair of cells often traces back to a com-
mon ancestor in which the original alteration occurred. Somatic changes
trace back to a descendant of the zygote; inherited changes trace back
to an ancestor of the zygote.
Evolutionary biologists have developed various methods to recon-
struct the history of descent—the phylogeny (Page and Holmes 1998;
Felsenstein 2003; Hall 2004). The methods essentially measure the rela-
tive likelihood of various ancestral relations between a set of cells, given
the pattern of shared and variant characters in those cells. The charac-
ters may be DNA sequence, patterns of DNA methylation, or any other
heritable characters.
An organism consists of a population of cells, whose cellular phy-
logeny describes its development and the lines of descent. Similarly, a
tumor consists of numerous cells, in which the cellular phylogeny re-
flects the heritable changes that drove progression.
These points about cellular phylogeny have been known for a long
time. But only recently has it been possible to reconstruct aspects of
organismal history on the time scale of cellular generations.
I limit my discussion here to a few examples. I focus on cases that
illustrate how phylogeny will help to understand the dynamics of pro-
gression and the patterns of age-specific incidence. This field will de-
velop rapidly (Frumkin et al. 2005), but one can already outline some of
the key concepts with regard to cancer dynamics and incidence (Shibata
and Tavare 2006).

VARIABLE METHYLATION PATTERNS

Epithelial cancers usually arise from the accumulation of heritable
changes in stem cell lineages. The historical relations between the stem
cells—their phylogeny—defines the shape of the cell lineage histories in