Page 228 - 20dynamics of cancer

11 Inheritance

Cancer progresses by the accumulation of heritable changes in cell lin-
eages. In the simplest case, all of the changes happen to the DNA of a
single somatic cell lineage. Starting with the initial cell, the carcinogenic
process develops through the sequential addition of genetic changes
that eventually gives rise to the tumor.
Many cancer biologists rightly object to this oversimplified view. The
heritable changes may often be epigenetic—genomic changes other than
DNA sequence—or physiological changes that persist (inherit) for many
cell generations. Changes may happen to multiple lineages, with car-
cinogenesis influenced by positive feedback between altered lineages.
But even this richer view still comes down to heritable changes in cell
lineages—almost necessarily so, because cells are the basic units, and
persistent change means heritable change. Disease arises at the level of
tissues, but the causes derive from changes to cells.
The first heritable carcinogenic changes may trace back to a somatic
cell that descended from the zygote, in which case the changes derive
purely from the somatic history of that organism. Or the origin of a
particular inherited variant may trace back to a germline cell in one of
the individual’s ancestors, in which case the inherited variant may be
shared by other descendants.
All of these descriptions turn on heritable change in lineages, that is,
on evolutionary change. Cancer has long been understood in terms of
somatic evolution within an individual’s cellular population. More re-
cently, the role of inherited germline variants has been studied in terms
of the evolutionary genetics of populations of individuals.
We can think about any particular variant, somatic or germline, in
two ways. First, the variant influences disease through its effect on
progression—the role of development that traces cause from genes to
phenotypes. Second, the phenotype influences whether, over time, the
variant lineage expands or goes extinct—the role of natural selection in
shaping the distribution of variants.
The following chapters focus on variants that originate in somatic
cells: in a particular cell, variants trace their origin back to an ancestral