Page 24 - 20dynamics of cancer

INTRODUCTION 9

easing the way for more such quantitative comparisons in the evalua-
tion of cancer genetics. Currently, most research compares genotypes
only in a qualitative way, ignoring the essential information about rates
of progression.
I continue Chapter 8 by applying my framework for comparisons be-
tween genotypes to data on incidence in laboratory populations of mice.
In one particular study, the mice had different genotypes for mismatch
repair of DNA lesions. I show how to set up and test a simple compara-
tive hypothesis about the relative incidence rates of various genotypes in
relation to predictions about how aberrant DNA repair affects progres-
sion. This analysis provides a guide for the quantitative study of rates
of progression in laboratory experiments. I finish this chapter with a
comparison of breast cancer incidence between groups that may differ
in many predisposing genes, each of small effect. Such polygenic in-
heritance may explain much of the variation in cancer predisposition. I
develop the quantitative predictions of incidence that follow from the
theory, and show how to make appropriate comparative tests between
groups that may have relatively high or low polygenic predisposition.
The existing genetic data remain crude at present. But new genomic
technologies will provide rapid increases in information about predis-
posing genetics. My quantitative approach sets the framework within
which one can evaluate the data that will soon arrive.
Chapter 9 compares incidence between different levels of chemical
carcinogen exposure. Chemical carcinogens add to genetics a second
major way in which to test comparative predictions about incidence in
response to perturbations in the underlying mechanisms of progres-
sion. I first discuss the observation that incidence rises more rapidly
with duration of exposure to a carcinogen than with dosage. I focus on
the example of smoking, in which incidence rises with about the fifth
power of the number of years of smoking and about the second power
of the number of cigarettes smoked. This distinction between duration
and dosage, which arises in studies of other carcinogens, sets a clas-
sic puzzle in cancer research. I provide a detailed evaluation of several
alternative hypotheses. Along the way, I develop new quantitative anal-
yses to evaluate the alternatives and facilitate future tests.
The next part of Chapter 9 develops the second classic problem in
chemical carcinogenesis, the pattern of incidence after the cessation of
carcinogen exposure. In particular, lung cancer incidence of continuing