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228 CHAPTER 11

altered risk of immigrants. Smoking (Doll 1998; Vineis et al. 2004) and
long-term exposure to certain carcinogens (Vineis and Pirastu 1997) also
cause significant environmental risk.
To determine the genetic component of risk, statistical studies com-
pare the frequencies of cancer occurrence between monozygotic twins,
dizygotic twins, other family members, and unrelated individuals (Licht-
enstein et al. 2000). In principle, such studies could separate the con-
tributions of shared genes, shared environment in the family, and dif-
ferences in environment between unrelated individuals. However, the
statistical power of such studies tends to be low, with wide confidence
intervals for the relative roles of genes and environment. This problem
is particularly severe for the rarer cancers because of low sample sizes
in such studies.
A large study from the Swedish Family-Cancer database provided nar-
rower confidence intervals for the proportions of cancer variance that
are explained by genes and environment (Czene et al. 2002). The esti-
mates for genetic contribution ranged from 1% to 53%, depending on the
type of cancer. These values may be lower limits, because certain types
of genetic variation could not be separated from the effects of a shared
environment. Confounding components include similar genotypes be-
tween parents, which would be classed as a shared environmental effect
rather than a genetic effect. In this study, Mendelian loci explain only
part of the total genetic contribution to cancer risk, indicating a signifi-
cant role for polygenic variation.
An interesting analysis of the Anglian Breast Cancer Study Group
study took a different approach to genetic predisposition (Pharoah et al.
2002). The authors first removed the two known Mendelian loci asso-
ciated with breast cancer—BRCA1 and BRCA2—from the analysis, and
then fitted the remaining risk distribution to a polygenic model in which
the small risks per variant allele are multiplied across loci. According
to the fitted model, the 20% of the population that has the highest level
of genetic predisposition has a 40-fold greater risk than the 20% of the
population with the lowest level of predisposition. The model also pre-
dicted that more than 50% of breast cancers occur in the 12% of the
population with the greatest predisposition. The known Mendelian loci
account for only a small proportion of the total genetic risk, with the
remainder being explained by polygenic variation.