Page 75 - 20dynamics of cancer

60 CHAPTER 4

number of steps to pass have a slower rise of incidence with age than
noninherited cases. Data comparing inherited and noninherited cases
in colon cancer (Ashley 1969a) and retinoblastoma (Knudson 1971) sup-
ported this prediction.
The third section takes up the kinds of changes that cause progres-
sion. Many authors have emphasized genetic changes by somatic muta-
tion. However, critics have argued against the somatic mutation theory,
favoring instead alternative mechanisms of genomic and physiological
change. For understanding the kinetics of progression, the alternative
mechanisms of change set different constraints on the rate parameters
of progression but do not alter the basic understanding of multistage
theory.
The fourth section highlights a puzzle about somatic mutation rates
and progression. Commonly cited values for the normal rate of somatic
mutation typically fall near 10 −6 mutations per gene per cell division.
Mutations to six particular genes in a cell lineage would occur with prob-
ability 10 −36 multiplied by the number of cell divisions in that lineage.
Historically, calculations of this sort with various assumptions about
the number of cell divisions and the number of cells at risk have sug-
gested that normal somatic mutation does not occur fast enough to
explain observed cancer incidence by progression through numerous
stages. That conclusion has led to various alternative theories about hy-
permutation, selection, clonal expansion of precancerous cell lineages,
and fewer numbers of mutations required for progression.
The fifth section reviews the theory of clonal expansion. Suppose a
mutation arises in a cell and that cell proliferates into a large clone. The
probability of a second mutation in a cell rises as the number of target
cells carrying the first mutation increases. Thus, clonal expansion can
greatly increase the rate at which mutations accumulate in cell lineages.
The sixth section continues discussion of cell lineages and mutation
accumulation. The rate at which cells divide is important because mu-
tations happen mostly during cell division. Tissues that grow early in
life and then slow to a very low rate of cell division predominantly suf-
fer childhood cancers rather than adult cancers. By contrast, epithelial
tissues with continual cell division throughout life suffer mostly adult
cancers and account for about 90% of human cancers. Cairns (1975)
emphasized that certain epithelial tissues renew from stem cells, a tis-
sue architecture that greatly reduces competition between lineages and