Gene expression profiling after radiation-induced DNA damage is strongly predictive of BRCA1 mutation carrier status

Purpose: The impact of the presence of a germ-line BRCA1 mutation on gene expression in normal breast fibroblasts after radiation-induced DNA damage has been investigated. Experimental Design: High-density cDNA microarray technology was used to identify differential responses to DNA damage in fibroblasts from nine heterozygous BRCA1 mutation carriers compared with five control samples without personal or family history of any cancer. Fibroblast cultures were irradiated, and their expression profile was compared using intensity ratios of the cDNA microarrays representing 5603 IMAGE clones. Results: Class comparison and class prediction analysis has shown that BRCA1 mutation carriers can be distinguished from controls with high probability (similar to85%). Significance analysis of microarrays and the support vector machine classifier identified gene sets that discriminate the samples according to their mutation status. These include genes already known to interact with BRCA1 such as CDKN1B, ATR, and RAD51. Conclusions: The results of this initial study suggest that normal cells from heterozygous BRCA1 mutation carriers display a different gene expression profile from controls in response to DNA damage. Adaptations of this pilot result to other cell types could result in the development of a functional assay for BRCA1 mutation status.