Page 260 - 20dynamics of cancer

INHERITANCE 245

Table 11.1 Variants in cases with multiple polyps and in controls

% carriers % carriers
Gene Mutation in cases in controls
APC E1317Q 2.42 1.25
CTNNB1 N287S 0.81 0.62
AXIN1 P312T 0.81 0.00
AXIN1 R398H 0.81 0.00
AXIN1 L445M 0.81 0.00
AXIN1 D545E 1.61 1.28
AXIN1 G700S 4.84 3.96
AXIN1 R891Q 3.91 2.93
hMLH1 G22A 0.81 0.21
hMLH1 K618A 3.22 2.07
hMLH2 H46Q 0.81 0.00
hMLH2 ex4SDS 0.81 0.00
hMLH2 E808X 0.81 0.00
Combined 24.9 11.5
From Tables 2 and 3 of Fearnhead et al. (2004), who contributed new data
and also collated data from various sources (Frayling et al. 1998; Lamlum et al.
2000; Webster et al. 2000; Dahmen et al. 2001; Taniguchi et al. 2002; Guerrette
et al. 1998; Tannergard et al. 1995). The mutation ex4SDS is an exon 4 splice
donor site. Mutations of the form α#β describe amino acid substitutions α → β
at codon position #.

that substitutions at position 618 cause functional changes (Shimodaira
et al. 1998). hMLH1 works in various heteromeric complexes, includ-
ing interaction with hPMS2 (Buermeyer et al. 1999; Fishel 2001); the
hMLH1 K618A mutation causes more than 85% loss of interaction be-
tween hMLH1 and hPMS2 (Guerrette et al. 1999).

DNA REPAIR VARIANTS
Earlier in this chapter, I mentioned that DNA repair efficiency varies
considerably in populations and has a large heritable component (Gross-
man et al. 1999; Cloos et al. 1999; Roberts et al. 1999). In addition, poor
repair efficiency consistently associates with an approximately 2–10-fold
increase in cancer risk (Berwick and Vineis 2000).
The previous section showed that rare variants at DNA mismatch re-
pair loci can predispose to colon cancer. The fact that rare variants can
predispose does not resolve whether the high heritability of repair ef-
ficiency and cancer predisposition arises mainly from relatively rare or