Genome-wide study of loss of heterozygosity using high density SNP arrays to identify breast cancer predisposition genes

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The genes responsible for the majority of breast cancer families remain unknown. The genes BRCA1 and BRCA2 can prevent the development of cancer and represent a class of gene known collectively as 'tumor suppressors'. One of the hallmarks of these genes is that they show loss of the normal copy of the gene in tumors that arise in individual carrying one inherited, mutated copy. The broad aim of this proposal is to exploit this phenomenon to identify novel tumor suppressor genes that predispose to familial breast cancer. This will be done by analyzing tumors from families that do not have either BRCA1 or BRCA2 mutations. Candidate tumor suppressor genes will be identified when tumors from different individuals in the same family all appear to have lost one copy of a gene, and retained the same copy, in a particular chromosomal region. We study tumours from non-BRCA1-2 breast cancer families using genetic techniques that are able to rapidly and accurately identify which parts of the chromosomes have been lost. Families will be identified in which all the tumors have lost exactly the same part of the chromosome. Next, we will exploit the fact that the entire sequence of the human genome is completed to find out which genes are located within the candidate region. We will then apply other technologies to identify which of these 'candidate genes' is actually responsible for the cancer in that family. Following this, we will investigate other families with a history of breast cancer to see how many can be accounted for by mutations in this gene. It is possible that we may identify more than on breast cancer gene using this powerful approach. Identification of new breast cancer predisposition genes would have major clinical relevance to the families directly affected, and much wider relevance if the same gene (or pathway) is later found to be involved in the causes of other familial or sporadic breast cancers.