Page 25 - 20dynamics of cancer

10 CHAPTER 1

cigarette smokers increases with approximately the fifth power of the
duration of smoking, whereas incidence among those who quit remains
relatively flat after the age of cessation. I provide a quantitative analysis
of alternative explanations. Finally, I argue that laboratory studies can
be particularly useful in the analysis of mechanisms and rates of pro-
gression if they combine alternative genotypes with varying exposure to
chemical carcinogens. Genetics and carcinogens provide different ways
of uncovering failure and therefore different ways of revealing mecha-
nism. I describe a series of hypotheses and potential tests that combine
genetics and carcinogens.
Chapter 10 analyzes age-specific incidence for the leading causes of
death. I evaluate the incidence curves for mortality in light of the multi-
stage theories for cancer progression. This broad context leads to a
general multicomponent reliability model of age-specific disease. I pro-
pose two quantitative hypotheses from multistage theory to explain the
mortality patterns. I conclude that multistage reliability models will de-
velop into a useful tool for studies of mortality and aging.

Part III discusses evolutionary problems. Cancer progresses by the
accumulation of heritable change in cell lineages: the accumulation of
heritable change in lineages is evolutionary change.
Heritable variants trace their origin back to an ancestral cell. If the
ancestral cell of a variant came before the most recent zygote, then the
individual inherited that variant through the parental germline. The
frequency of inherited variants depends on mutation, selection, and the
other processes of population genetics. If the ancestral cell of a variant
came within the same individual, after the zygote, then the mutation
arose somatically. Somatic variants drive progression within an individ-
ual.
Chapter 11 focuses on germline variants that determine the inher-
ited predisposition to cancer. I first review the many different kinds
of inherited variation, and how each kind of variation affects incidence.
Variation may, for example, be classified by its effect on a single lo-
cus, grouping together all variants that cause loss of function into a
single class. Or variation may be measured at particular sites in the
DNA sequence, allowing greater resolution with regard to the origin of