Meeting the challenges of breast cancer genetics research from Down Under
Despite the early promise delivered by the mapping of the first breast cancer susceptibility gene in 1988, and the isolation of the two major susceptibility genes, BRCA1 and BRCA2, respectively, advances in our understanding of the complexity of breast cancer genetics has been relatively slow in the last decade. As with all complex diseases, a major obstacle has been the acquisition of sufficient resources with the depth and breadth to provide the power needed to find additional susceptibility genes, identify modifiers of BRCA1 and BRCA2, predict the clinical consequences for carriers and address other questions relating to the biology and clinical aspects of familial breast cancer.
For this reason, we started the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) in Australia in 1997. Since then we have collected almost 9000 bloods and more than 7000 pathology reports, from almost 1000 multiple-case breast cancer families. We have also banked more than 400 fresh frozen prophylactic and tumour specimens. Since its inception, kConFab material has been available to anyone in the world with approved projects, and now supports about 50 projects based in Australia, the US and Europe.
My own research is very heavily dependent on kConFab. We have demonstrated that a rare mutation in the ATM gene, identified in two kConFab families, confers a moderately-high risk of breast cancer and have made a knock-in mouse to examine the effects of this mutation on mammary tumorigenesis. We have also used pathology and loss of heterozygosity analysis to help to classify ‘unclassified’ variants (UVs) of BRCA1 and BRCA2 as neutral or deleterious. We are extending this project to include expression profiling of lymphoblastoid cell lines and archival pathology blocks from carriers of UVs, as a further means of classifying these variants. We are also using expression profiling to stratify non-BRCA1/2 tumours, in order to try to facilitate the identification of additional breast cancer susceptibility genes. Recent results from the laboratory will be presented, as well as some perspectives on how, and why, we do genetic research Down Under.