Page 259 - 20dynamics of cancer

244 CHAPTER 11

MULTIPLE COLON ADENOMAS
Fearnhead et al. (2004) collated data on 124 individuals with multi-
ple adenomatous polyps. They screened those individuals for germline
DNA variants in five genes known to influence colon cancer progression,
and found 13 different variants. They compared the frequency of those
13 variants in the 124 cases with the frequency in 483 random control
individuals.
Table 11.1 shows the frequencies of the 13 variants in cases and con-
trols. These results suggest that many rare variants, each of small effect,
contribute significantly to the heritability of cancer. In this study, almost
all of the variants were single amino acid substitutions. Each such small
change in protein shape and charge may contribute a small amount to
disease. Many such changes, each rare, may in the aggregate explain
much of the genetic basis of disease.
Fearnhead et al. (2004) support their argument that single amino acid
substitutions in proteins contribute to disease by evaluating the func-
tional changes for many of the mutations listed in Table 11.1. Almost
all of the variants occur in regions of their proteins known to have im-
portant functional roles in pathways that are often disrupted in tumors.
I briefly summarize two examples from Fearnhead et al.’s (2004) discus-
sion.
The APC variant E1317Q alters charge in the region that binds to β-
catenin. Mutation of the APC regulatory pathway appears to be a com-
mon first step in adenoma formation (Kinzler and Vogelstein 2002). APC
represses β-catenin, which may have two different consequences for cel-
lular growth. First, β-catenin may enhance expression of c-Myc and other
proteins that promote cellular division. Second, β-catenin may play a
role in cell adhesion processes, effectively increasing the stickiness of
surface epithelial cells. In either case, repression of β-catenin reduces
the tendency for abnormal tissue expansion. In tumors, somatic mu-
tations in APC usually include domains involved in binding β-catenin,
releasing β-catenin from the suppressive effects of APC (Kinzler and
Vogelstein 2002).
The hMLH1 variant K618A alters the charge of a highly conserved
region of this DNA mismatch repair protein. Several deleterious muta-
tions have been reported in this region (Wijnen et al. 1996; Peltomaki
and Vasen 1997; Mitchell et al. 2002), and studies in yeast demonstrated