Page 89 - 20dynamics of cancer

74 CHAPTER 4

Colonic epithelium renews one to two times per week, so stem cells prob-
ably divide 50–100 times per year. Over a lifetime, the number of stem
4
cell divisions to renew the colonic epithelium may be near 10 . Other
tissues renew less frequently, perhaps needing somewhere around 10 2
4
3
to 10 stem cell divisions. Figure 4.2 shows that 10 stem cell divisions
can explain 4–6 hits within the normal range for somatic mutation; 10 3
cell divisions can explain 3–4 hits.
Hypermutation may indeed play a key role in many cases. However,
in looking at Figure 4.2 and the calculations in Calabrese et al. (2004),
the argument against standard mutational processes does not seem as
strong as is sometimes presented.
The debate about the role of hypermutation continues in the current
literature. I delay discussion of those arguments until a later section,
so that I can first fill in important steps in the historical development of
the subject.

4.5 Clonal Expansion of Premalignant Stages
Muller (1951, p. 131) described the problem clearly. In the accumula-
tion of a series of somatic mutations within a cell lineage:

The time element would constitute an influential factor unlike what
is found to be the case in ordinary mutation production; for cells
in which one step had occurred might because of it have prolif-
erated sufficiently, by the time of a later treatment, to give better
opportunity for another step to occur on top of the first.

Nordling (1953) made a similar comment, but, having cited Muller in
another context, may well have obtained the idea from the quote here.
Platt (1955) independently came to the same idea when thinking about
the long latent period between exposure to a carcinogen and occurrence
of cancer. Platt argued that
If the carcinogen simply acts by causing cells to proliferate, so that
instead of dividing by mitosis x times in 20 years, they have been
stimulated to divide x × y times (y > 1), and if, as Sonneborn
seems to have shown in paramecium, the chromosomal substance
duplicates more and more inaccurately as the number of divisions
is increased, and if this kind of nuclear aberration could cause a
malignant change in the cell, the reason for the latent period would
be explained.