Page 176 - 20dynamics of cancer

GENETICS OF PROGRESSION 161

because each particular genetic variant has only a minor effect, shifting
incidence by only a small amount.
Comparison of the rate of progression between different genotypes
could provide information about the ways in which genetic variants com-
bine to influence cancer incidence. However, if individual genetic vari-
ants cause only small changes, then how can one identify genotypes
that are sufficiently different with regard to cancer predisposition? One
approach is to identify a group of genetically predisposed individuals
by studying the first-degree relatives of those who develop cancer early
in life. This high-risk group can be compared with a control group of
low-risk individuals who do not have an affected first-degree relative.
In a comparison between high- and low-risk groups, two outcomes
would suggest polygenic predisposition to cancer. First, the high-risk
group must have early onset of cancer as measured by age-specific inci-
dence. Second, one must rule out the possibility that major mutations to
single genes, such as APC, explain most of the difference in age-specific
incidence.
A study of breast cancer showed that those with affected first-degree
relatives progress more rapidly than do the controls (Figure 8.10). In-
terestingly, the earlier the age at which a first-degree relative develops
breast cancer, the greater the incidence of those at risk (Peto and Mack
2000).
The slopes of the incidence curves form a set of parallel acceleration
curves (Figure 8.11). Those groups whose first-degree relatives had can-
cer at a relatively earlier age had both greater incidence and lower accel-
eration. In terms of multistage theory, this negative association between
incidence and acceleration arises when the genetically predisposed fast
progressors must pass through fewer rate-limiting stages than the slow
progressors.
A difference in the number of stages in progression can arise in at least
four ways. First, the fast progressors may have genotypes that advance
them one or more stages in progression. An advance in initial stage
seems to explain the difference in incidence in the single-gene defects,
such as retinoblastoma and FAP.
Second, the fast progressors may have less efficient DNA repair and a
higher somatic mutation rate, causing progression to advance so rapidly
through some stages that those stages are no longer rate-limiting.