Page 242 - 20dynamics of cancer

INHERITANCE 227

prior knowledge about the functional consequences of particular amino
acid substitutions.
Many factors influence age of onset, so the PolyPhen scoring on sin-
gle variants will provide only a small amount of information about pre-
dicted risk and age of onset. The value of the analysis may come from
hypotheses about which amino acid sites and which kinds of biochemi-
cal function affect DNA repair efficacy, and how those changes in efficacy
influence cancer progression. Such hypotheses could be tested in labo-
ratory animals, in which one could construct genotypes with particular
amino acid substitutions.

COMBINED EFFECT OF VARIANTS AT MULTIPLE SITES
Cancer often aggregates in families, suggesting a strong inherited
component that predisposes individuals to disease. In two well-studied
cancers, breast and colon, only about 10–20% of the inherited compo-
nent can be explained by known variants (Anglian Breast Cancer Study
Group 2000; de la Chapelle 2004). Those known variants include BRCA1
and BRCA2 for breast cancer and APC and the mismatch repair genes
for colon cancer. Each of those variants causes a large change in the
incidence curve. The large effect of such variants makes them relatively
easy to study: compare the incidence curves between genotypes with
and without the variant. A small sample provides sufficient power to
observe the large effect.
Many other variants, each with small effect on incidence, may also oc-
cur. However, finding such variants is difficult. One must first identify a
candidate variant, and then compare incidence between genotypes with
and without the variant in large samples. Such studies remain beyond
what can easily be accomplished, even with advancing technology.

STATISTICAL STUDIES OF INHERITANCE
In the absence of direct knowledge about many genes that predispose
to cancer, statistical studies have analyzed how environmental and ge-
netic variation contribute to differences in cancer risk. For example,
reflecting environmental effects, immigrants take on the risk of colon
cancer that is specific for their new home (Haenszel and Kurihara 1968).
The risk of developing colon cancer for an individual in a specific ge-
ographical region is strongly associated with levels of meat consump-
tion (Armstrong and Doll 1975), so changes in diet might explain the