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250 CHAPTER 11

The effect per variant of rare versus common variants remains un-
known. Rare alleles will likely have greater effects than the common
alleles if variant frequency depends on mutation, drift, and selection
against deleterious effects. By contrast, common alleles may have larger
effects if variants either have variable consequences depending on envi-
ronment or genetic background, or if variants have beneficial pleiotropic
effects that offset the deleterious traits that increase cancer incidence.
It will not be easy to work out the relative contribution of different
variants and how variants combine to determine disease. But much at-
tention will continue to focus on this problem. Through cancer studies,
we will gain insight into the genetic basis of variability in key functional
components, such as DNA repair and tissue regulation via control of the
cell cycle. By study of functional components and their genetic basis of
variation in efficiency, and how the components interact to determine
disease, we will begin to understand how evolution has shaped the age-
specific curves of failure. Through those curves of failure, we can ana-
lyze the evolutionary design of reliability that sets the nature of disease
and aging.

11.4 Summary

The first part of this chapter described how inherited genetic variants
affect the age of cancer onset. In the future, new genomic technologies
will measure genetic variation with far greater resolution. To interpret
those high-resolution measurements of genetic variation, we will have
to connect the observed genetic variation to the causes of cancer. Such
connections can only be made by studying how genetic variants shift the
age-specific incidence. In the second part of the chapter, I analyzed the
population frequency of predisposing genetic variants in light of various
evolutionary forces. I suggested that studies of cancer predisposition
may lead the way in understanding the structure of inherited genetic
variation for age-specific diseases.
The next chapter turns to the somatic evolution of cancer within in-
dividuals. Most human cancers arise in tissues that renew throughout
life. Those tissues often derive from stem cells. I review the biology of
stem cells and how the shape of stem cell lineages in renewing tissues
affects the progression of cancer.