Page 94 - 20dynamics of cancer

HISTORY OF THEORIES 79

SELECTION BETWEEN VARIANTS
Cairns (1975, p. 200) noted that an increase in the mutation rate per
cell division would speed up progression. However, in epithelial tissues
renewed by stem cells, each new mutation would remain confined to a
single linear history of descent. Thus, Cairns stated that
Unless such mutagenic mutations confer some survival advantage,
however, they will remain confined to the stem cells in which they
arise ... Probably more important, therefore, are mutations that
affect the interactions of a cell with its neighbours. Any mutation
that gives a stem cell the ability to move out of its compartment
in an epithelium may cause it to form an expanding clone of stem
cells.

This quote emphasizes the theory of clonal expansion. However, the
early theories of clonal expansion focused only on the consequences
of expansion. By contrast, Cairns emphasizes the processes that limit
competition, and the types of cellular changes that would bypass those
limits and promote competition between lineages. Put another way, the
early theories focused on the consequences of selection, and the later
theories beginning with Cairns emphasized the mechanisms involved in
such selection.
The debate continues about the relative importance of mutators ver-
sus selection and clonal expansion (Sieber et al. 2005). Tomlinson et al.
(1996) reviewed the issues in favor of selection, arguing against the need
to invoke mutators in order to explain the incidence of cancer.

4.8 Epigenetics: Methylation and Acetylation

Many theoretical issues have turned on the rate of transition between
key stages in progression. I mentioned the concerns that the commonly
accepted somatic mutation rate of about 10 −6 mutations per gene per
cell division seemed too low to some investigators to explain how mul-
tiple changes could accumulate.
One recurring problem concerns the definition of “mutation” (Bur-
dette 1955). I am interested in kinetics, so I tend to follow those au-
thors who use the term “mutation” rather loosely for heritable genomic