ABSTRACT
For many years the main focus of the research effort into the inherited basis of breast
cancer was the search for single, strong, but rarely mutated predisposing genes that cause
a subset of the disease with Mendelian inheritance. More recently, attention has switched
to the systematic study of common genetic variation in complex disease susceptibility
with the promise of a “polygenic” approach to the prevention and treatment of common
diseases. This change of focus has been enabled by the completion of the human genome
sequence and the subsequent generation of detailed information about the range of
genetic differences between individuals. Some have claimed that the greater under-
standing of genetic risk factors and their interactions with the environment will allow
diseases to be predicted and to be prevented at both individual and population levels, by
directing interventions at individuals shown to be at high risk (1,2). Others are less sure
(3-5): in particular, they question whether molecular testing for common genetic variants
can have sufficient predictive power to be of practical use either for the individual or for
defining risk groups in the population at large. In this chapter, I will review the evidence
for the polygenic model of breast cancer susceptibility, discuss progress toward
identifying low-penetrance alleles, and comment on the clinical utility and public health
relevance of these alleles.
