Page 158 - 20dynamics of cancer

8 Genetics of Progression

Genes affect cancer to the extent that they alter age-specific incidence.
Thus, the most powerful empirical analysis compares age-specific inci-
dence between normal and mutated genotypes. This chapter describes
comparative studies between genotypes.
The first section compares mutant and normal genotypes in human
populations. I begin with the classic study of retinoblastoma. An inher-
ited mutation in the Rb gene causes a high incidence of bilateral retinal
tumors. Individuals who do not inherit a mutation suffer rare unilat-
eral tumors. The age-specific acceleration of unilateral cases is one unit
higher than the acceleration of bilateral cases, consistent with the pre-
diction that most of the individuals who suffer bilateral retinoblastoma
were born advanced by one stage in progression because of an inherited
mutation.
A similar comparison between inherited and sporadic cases of colon
cancer shows that the sporadic cases have an acceleration approximately
one unit greater than inherited cases. The decrease in acceleration for
individuals who inherit a mutation to the APC gene supports the hy-
pothesis that such mutations cause their carriers to be born one stage
advanced in progression.
The second section compares incidence between different genotypes
in laboratory animals. The controlled genetic background makes clearer
the causal role of particular mutations in shifting age-specific incidence.
I describe the quantitative methods needed to test hypotheses with the
small sample sizes commonly obtained in lab studies. I then present a
full analysis of one example: the change in age-specific incidence and
acceleration between four genotypes with different knockouts of DNA
mismatch repair genes. Knockouts that cause a greater increase in mu-
tation rate had earlier cancer onset and a lower age-specific acceleration.
The lower acceleration suggests some hypotheses about how the mis-
match repair mutations affect the rate of cancer progression.
The third section compares breast cancer incidence between human
groups classified by the age at which a first-degree relative developed
the disease. The earlier the age of onset for the affected first-degree