Introduction

A major challenge for molecular and epidemiological science is to unravel the molecular genetic basis of chronic disease. The past 30 years have seen considerable progress in understanding the molecular genetics of diseases that are inherited according to Mendelian rules, that is, those in which mutations in a single gene have a large effect on disease risk (see Chapter 10). However, little is known about complex disease, which results from the combined effects of many genes, that is, diseases which show polygenic inheritance. Rapid advances in our understanding of human genome architecture together with technological developments may help us meet this challenge successfully. This will bring new insights into disease etiology, which, in turn, will help in the development of new methods for disease prevention and treatment. As a result of these advances, it may also become possible to target interventions to individuals at greatest risk of disease. In this chapter we will review the evidence for the polygenic model of breast cancer susceptibility and discuss the implications of the model for disease prevention in the population. We will contrast this with the potential impact of preventive interventions targeted at women with single gene disorders who are at high risk of disease.

Genetic models of breast cancer susceptibility

It is likely that the inheritance of most common cancers is polygenic. Breast cancer, like other common cancers, exhibits some degree of familial clustering, with disease being approximately twice as common in first-degree relatives of cases (Amundadottir et al. 2004; Collaborative Group on Hormonal Factors in Breast Cabcer, 2001).