Page 255 - 20dynamics of cancer

240 CHAPTER 11

into account the fact that the age of reproduction in the past was proba-
bly somewhat lower than in modern societies. In this case, qpr ≈ 10 −5 ,
which is again fairly close to the standard estimate for the mutation rate.

Hereditary nonpolyposis colon cancer.—Mutations in the DNA mismatch
repair (MMR) system lead to hereditary nonpolyposis colon cancer (HN-
PCC) (Boland 2002). Mutations in several MMR genes cause an increase
in the somatic mutation rate, and more frequent somatic mutations lead
to a high probability of early-onset cancer. The median age of diagnosis
for HNPCC is about 42 years (Lynch et al. 1995). The frequency of cases
is at least of the order of 10 −3 , but may be more because HNPCC can be
difficult to distinguish from colon cancers that arise in the absence of
MMR defects.
Setting the level of reproductive loss at r = 10 −1 , the rate of removal
of MMR mutations, qpr,is 10 −4 or higher. This value would indicate a
high mutation rate if there were only one MMR locus. However, muta-
tions that increase the risk of developing HNPCC have been identified in
five MMR loci so far (Boland 2002), and mutations that influence HNPCC
may also occur in other MMR genes. There are 22 genes in the core MMR
pathway (Mohrenweiser et al. 2003). The effective mutation rate is nu,
where n is the number of MMR loci and u is the mutation rate per locus.
Using a range for n of approximately 3–10, we obtain a range for the
mutation rate per locus of approximately 1–3 ×10 −5 .

Neurofibromatosis type 1.—Inherited mutations in the neurofibromato-
sis1(NF1) gene cause a variety of symptoms with variable penetrance
(Gutmann and Collins 2002). Carriers may express various nonlethal
deformities: numerous flat, pigmented skin spots; freckling; pigmented
nodules of the iris; and soft, fleshy peripheral tumors that arise from
nerves (neurofibromas). Several other complications develop, including
seizures, learning disabilities, and scoliosis.
NF1 is among the most common dominantly inherited diseases of
humans. Gutmann and Collins (2002) estimated prevalence of about
3×10 −4 , based on several earlier studies (Crowe et al. 1956; Huson et al.
1989; Sergeyev 1975; Samuelsson and Axelsson 1981). Carriers almost
always express some of the symptoms—a penetrance, p, of nearly one.
The disease rarely reduces potential fertility, but actual reproductive
success of carriers has been estimated to be about one-half of normal