Page 246 - 20dynamics of cancer

INHERITANCE 231

et al. (2003). In 74 repair genes from various pathways, the average fre-
quency of the wild-type allele is approximately 80%, with the remaining
20% comprised of different allelic variants. Among the 148 alleles per
person at the 74 repair loci, the average number of allelic variants is
expected to be approximately 30. Presumably, each individual carries a
very rare or unique genotype.
In summary, small variations in DNA repair are highly heritable, DNA
repair efficiency is correlated with cancer risk, and there are widespread
amino acid polymorphisms in the known repair genes. The next step
will be to link those polymorphisms to variations in the biochemistry of
repair, providing a mechanistic understanding of how genetic variation
influences an important aspect of cancer predisposition (de Boer 2002).

AGE-SPECIFIC INCIDENCE
The polymorphisms that occur in DNA repair genes hint at variations
in cellular physiology that may be very common. The connection be-
tween DNA repair efficiency and cancer seems plausible, because so-
matic mutations and chromosomal aberrations probably have a key role
in cancer progression. However, at present, we cannot make a simple
mechanistic connection between repair efficacy and the rate of progres-
sion to cancer.
Currently, the most interesting studies of multisite variants and age-
specific incidence link aggregation of cases in families to age of onset.
Presumably, familial cases that rule out known major single-site variants
arise from multisite variants shared by relatives.
Peto and Mack (2000) noted that women who are at high risk of devel-
oping breast cancer show an approximately constant incidence of cancer
per year after a certain age, whereas in most individuals incidence rises
significantly with age (Figure 11.6). This pattern appears in three differ-
ent classes of susceptible individuals after the age at which a particular
patient develops cancer. I refer to the individual who first has cancer as
the patient or the index case, and the age of this first diagnosis as the
index age.
In the first class, an index case with monolateral breast cancer has
an annual risk of developing cancer in the other (contralateral) breast
of approximately 0.7% per year after the index age. A different study
found a similar result, with risk in the contralateral breast of about 0.5%
per year after the initial cancer (Figure 11.7).