Page 248 - 20dynamics of cancer

INHERITANCE 233

cancers arise in a susceptible minority whose incidence, at least on av-
erage, has increased to a high constant level at a predetermined age that
varies between families.”
But why should predisposed individuals have constant annual risks
after a certain age? Individuals who are not predisposed to breast cancer
show an increasing risk with age, and the same is true for the other most
common types of epithelial cancer when risk is measured in the absence
of information about genetic predisposition.
Frank (2004d) proposed the following explanation for Peto and Mack’s
(2000) observations. Suppose, at birth, that each of L different cell lin-
eages in the breast has n rate-limiting steps remaining before cancer.
I have discussed previously that, as individuals age, their cell lineages
may progress independently. Over time, the various lineages form a
distribution of stages: some still have n stages remaining before cancer,
others have progressed part way and have, for example, n − a stages
remaining.
If some cell lineages in an individual have passed through all but the
final stage in cancer progression, with only one stage remaining, then
that individual’s annual risk is constant—the risk is just the constant
probability of passing to the final stage. Families that have an increased
predisposition may progress through the first n − 1 stages quickly; sub-
sequently, their annual risk is the constant probability of passing the
final stage. Families with low genetic risk move through the early stages
slowly: in middle or late life, members of those families typically have
more than one stage to pass and so continue to have an increasing rate
of risk with advancing age.
If the early stages in cancer progression involve somatic mutations
or chromosomal aberrations, impaired DNA repair efficiency could ex-
plain why families with increased predisposition move quickly through
the early stages. When they have progressed through the early stages,
individuals from those families have a high constant risk later in life
while awaiting the final transition. By contrast, better repair efficiency
slows the transition through the early stages. Slow transitions early in
life mean more stages to pass through later in life. With more stages
remaining, individuals at low risk continue to show an increase in inci-
dence with age (Frank 2004d).