Four novel breast cancer susceptibility genes are identified in a study published online in Nature on May 27th. The large, international, genome-wide association study from the Breast Cancer Association Consortium suggests that there might be many more genes that affect a woman's risk of breast cancer. These findings considerably increase our knowledge of the genetic component of breast cancer risk, much of which has been uncharacterised despite the identification of the best known susceptibility genes, BRCA1 and BRCA2, in the 1990s.

BRCA1 and BRCA2, and other genes that carry rare mutations such as ATM, account for less than 25% of the familial risk of breast cancer. It is believed that a combination of many additional genes, each playing a smaller role, also contribute to the disease. The first of these “polygenes” to be unequivocally identified was CASP8, which was reported by the Breast Cancer Association Consortium earlier this year.

To look for further susceptibility alleles Douglas Easton and colleagues in Cambridge, UK, initiated a study of the whole genome, in which the 22 groups in the Breast Cancer Association Consortium came together again to test the most likely 30 genetic variants in 21,860 patients and 22,578 controls from around the world. Georgia Chenevix-Trench and colleagues at the Queensland Institute of Medical Research, who are co-authors on the Nature paper, contributed data from kConFab and controls from the Australian Ovarian Cancer Study, and also from the Australian Breast Cancer Family Study, which is led by Professor John Hopper in Melbourne. kConFab cases are particularly informative for these studies because of their strong family history of breast cancer which means that they provide more statistical power than a case with no family history.

The authors identified four genes associated with genetic susceptibility to breast cancer (FGFR2, TNRC9, MAP3K1 and LSP1). Further investigation indicates that many additional susceptibility alleles of more modest effect may also be identifiable by this approach of studying the whole genome without any prior hypothesis about which genes may be involved.

Although there is no immediate clinical implication of this study, it is hoped that within 5-10 years these sorts of studies may lead to the development of a test that could be used for all willing women in the population, to determine who is at the highest risk of breast cancer (regardless of their family history) and could be offered more intensive screening to detect breast tumours early.