Page 27 - 20dynamics of cancer

12 CHAPTER 1

Chapter 13 analyzes different shapes of cell lineages with regard to
the accumulation of heritable change and progression to cancer. In de-
velopment, cell lineages expand exponentially to produce the cells that
initially seed a tissue. By contrast, once the tissue has developed, each
new mutation usually remains confined to the localized area of the tis-
sue that descends directly from the mutated cell. Because mutations
during development carry forward to many more cells than mutations
during renewal, a significant fraction of cancer risk may be determined
in the short period of development early in life. Once the tissue forms
and tissue renewal begins, the particular architecture of the stem-transit
lineages affects the accumulation of heritable variants. I analyze vari-
ous stem-transit architectures and their consequences. Finally, I discuss
how multiple stem cells sometimes coexist in a local pool to renew the
local patch of tissue. The long-term competition and survival of stem
cells in a local pool determine the lineal descent and survival of heritable
variants.
Chapter 14 describes empirical methods to study cell lineages and
the accumulation of heritable change. Ideally, one would measure her-
itable diversity among a population of cells and reconstruct the cell
lineage (phylogenetic) history. Historical reconstruction estimates, for
each variant shared by two cells, the number of cell divisions back to the
common ancestral cell in which the variant originated. Current studies
do not achieve such resolution, but do hint at what will soon come with
advancing genomic technology. The current studies typically measure
variation in a relatively rapidly changing aspect of the genome, such
as DNA methylation or length changes in highly repeated DNA regions.
Such studies of variation have provided insight into the lineage history
of clonal succession in colorectal stem cell pools and the hierarchy of
tissue renewal in hair follicles. Another study has indicated that greater
diversity among lineages within a precancerous lesion correlate with a
higher probability of subsequent progression to malignancy.
I finish Chapter 14 with a discussion of somatic mosaicism, in which
distinct populations of cells carry different heritable variants. Mosaic
patches may arise by a mutation during development or by a mutation
in the adult that spreads by clonal expansion. Mosaic patches sometimes
form a field with an increased risk of cancer progression, in which mul-
tiple independent tumors may develop. Advancing genomic technology
will soon allow much more refined measures of genetic and epigenetic