Page 261 - 20dynamics of cancer

246 CHAPTER 11

common alleles. The existing data do not settle the issue. Two lines of
evidence provide clues.

FREQUENCY DISTRIBUTION OF VARIANTS
Mohrenweiser et al. (2003) summarized genetic variation across 74
DNA repair loci. Figure 11.9 shows that the rare, intermediate, and
common alleles contribute equally to the variance in allele frequency.
To understand what this means, consider how to calculate the genetic
variance in allele frequencies.
The contribution of a variant allele with frequency p i to the variance
at its locus is v i = p i (1 − p i ). A rare allele at frequency p i = 0.01
contributes v i ≈ 0.01 to the frequency variance. A common allele at
frequency p i = 0.11 contributes v i ≈ 0.1 to the frequency variance, or
about an order of magnitude more than the rare variant. If there were
ten times as many rare variants as common variants, then the rare and
common variants would contribute equally to the total variance.
Figure 11.9 shows that there are more rare variants than common vari-
ants. The excess of rare variants explains why the total contribution to
the variance in allele frequency is about the same for rare, intermediate,
and common alleles.
These calculations provide information about the frequency of vari-
ant alleles. However, these data do not connect the different variants
to their consequences for disease. Inevitably, some of the variants will
have little or no effect, whereas others may significantly increase risk.
The common types are unlikely to be severely deleterious, but beyond
that, no strong conclusions can be made about the effects of the vari-
ant alleles. The data on colon cancer in the previous section show that
rare variants can influence predisposition. The next section shows that
combinations of common variants may also significantly affect predis-
position.

MULTIPLE VARIANTS INCREASE PREDISPOSITION
A pathway such as a particular type of DNA repair forms a quanti-
tative trait that protects against cancer progression. Certain individual
polymorphisms may each reduce the efficacy of the pathway by a small
amount, and consequently cause a small and perhaps undetectable in-
crease in cancer risk. In combination, multiple polymorphisms may sig-
nificantly reduce efficacy and consequently cause a significant rise in