Identification of Candidate Breast Cancer Susceptibility Genes Using a cDNA Microarray/CGH Approach

摘要

Familial breast cancer accounts for 15 to 35% of all breast cancers. Mutations in a number of genes are now known to cause susceptibility to breast cancer; the most notorious are the BRCA1 and BRCA2 genes. However, it has become evident that not all (or even the majority) of familial breast cancer families can be attributed to mutations in BRCA1 and BRCA2. In a recent study by the Breast Cancer Linkage Consortium, only one third of families with four or five cases of female breast cancer and no cases of ovarian cancer carry mutations in either BRCA1 and BRCA2. Smaller familial clusters are much more common than families with large numbers of cases, suggesting that a substantial proportion of familial clustering is not accounted for by mutations in BRCA1 and BRCA2; therefore, there is a great need to discover other genes that contribute to this disease. We hypothesize that a heterozygous deletion in constitutive DNA or a homozygous deletion in multiple tumors and tumor types from a cancer-prone family will represent a strong candidate cancer predisposing gene. To establish this proof of principle, we have successfully developed a fluorescent-based DNA microarray assay to identify deletions, as small as a single exon, in heterogeneous tumor DNA.