Genomics and breast cancer: the different levels of inherited susceptibility

Abstract

Our understanding of inherited breast cancer susceptibility has changed dramatically over the last 5 years, with the discovery of many genes in which mutations influence the risk of developing breast cancer. These fall into three main groups: genes in which mutations confer a high risk of developing cancer, but where such mutations are rare; uncommon mutations in genes conferring a moderate increase in risk (odds ratios of approximately 2–4), and common polymorphic variants which each confer only slight risk alterations (odds ratios rarely above 1.2 for variants conferring increased risk). The discovery of these genes and loci was predicated on linkage analysis (for high-risk genes), screening for mutations in candidate genes selected because they were involved in functional pathways related to BRCA1 and BRCA2 function (moderate risk), and genome-wide association studies (low penetrance polymorphisms). However, with this increased knowledge comes the difficulty of knowing how this information may best be utilized in clinical practice. The review by Ripperger et al1 in this edition of the Journal examines the current knowledge of newly identified moderate and low risk susceptibility genes, classifying the genes involved in inherited breast cancer susceptibility into the categories described above. The tables and diagrams are helpful in indicating the relative frequency and penetrance for breast cancer of genetic variants in these different categories, and give some indication of the proportion of the disease burden associated with mutations in each gene. The discovery of lower penetrance genes2 indicates that inherited breast cancer susceptibility is due to a number of genetic factors, and it may well be that the familial clusters of breast cancer not due to mutations in BRCA1 and BRCA2, originally attributed to BRCA3, are in fact due to a combination of the effects of lower penetrance gene mutations and environmental factors. Healthcare providers will have the dilemma of deciding whether it will be cost-effective to introduce population screening of variants of these low penetrance genes and what level of risk would justify medical intervention. Inheritance of one low penetrance risk-conferring polymorphic allele may only confer a very minor increase in risk of developing cancer, but individuals who have inherited several high-risk polymorphic variants may be at significantly increased risk. It has recently been argued, for instance,3 that individuals who have, say, six ‘high'-risk alleles, may have a sufficiently increased risk to justify initiating mammographic surveillance 10 years before the generally recommended age for women in the general population, and women with six low risk alleles could start screening at a later age.