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230 1.4 patient’s monozygotic twin CHAPTER 11

Incidence per 100 individuals 1.0 mothers and sisters by patient’s age at diagnosis
1.2

0.8
patient’s contralateral breast
0.6
0.4
diag. at 50
0.2
0.0
30
20 diag. at 30 diag. at 40 40 general population 70
50
60
Age
Figure 11.6 Schematic summary of breast cancer incidence in individuals with
varying levels of relatedness to an index case. Redrawn from Peto and Mack
(2000).

heritable component (Grossman et al. 1999; Cloos et al. 1999; Roberts
et al. 1999). Measures of variability and heritability are statistical de-
scriptions of the genetics of repair. Recent studies have made the first
steps toward understanding the mechanistic relations between genetic
variants and altered phenotypes.
Many genes in the five key repair pathways for different types of DNA
damage are known (Bernstein et al. 2002; Thompson and Schild 2002;
Mohrenweiser et al. 2003), so genetic variants can be identified by se-
quencing the loci involved. Specific variants can also be constructed,
and their physiological consequences tested in cell-based assay systems.
Mohrenweiser et al. (2003) list 22 genes in the core pathway of the MMR
system. This system primarily corrects mismatches and short insertion
or deletion loops that arise during replication or recombination (Hsieh
2001). The MMR system increases the accuracy of replication by a factor
of 100–1,000.
Eighty-five different variants have been found in seventeen different
MMR genes that were screened in at least fifty unrelated individuals
(Mohrenweiser et al. 2003). Of those variants, 38% occurred at a fre-
quency of 2% or more; 21% occurred at a frequency of 5% or more;
and 12% occurred at a frequency of 20% or more. The other DNA re-
pair pathways provided similar results, as summarized by Mohrenweiser