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A large number of rare sequence variants of unknown clinical significance have been identified in the breast cancer susceptibility genes,  BRCA1  and  BRCA2.  Laboratory-based methods that can distinguish between carriers of pathogenic mutations and non-carriers are likely to have utility for the classification of these sequence variants. To identify predictors of pathogenic mutation status in familial breast cancer patients, we explored the use of gene expression arrays to assess the effect of two DNA–damaging agents (irradiation and mitomycin C) on cellular response in relation to  BRCA1  and  BRCA2  mutation status. A range of regimes was used to treat 27 lymphoblastoid cell-lines (LCLs) derived from affected women in high-risk breast cancer families (nine  BRCA1 , nine  BRCA2 , and nine non- BRCA1/2  or BRCAX individuals) and nine LCLs from healthy individuals. Using an RNA–pooling strategy, we found that treating LCLs with 1.2 µM mitomycin C and measuring the gene expression profiles 1 hour post-treatment had the greatest potential to discriminate  BRCA1 ,  BRCA2 , and BRCAX mutation status. A classifier was built using the expression profile of nine QRT–PCR validated genes that were associated with  BRCA1 ,  BRCA2 , and BRCAX status in RNA pools. These nine genes could distinguish  BRCA1  from  BRCA2  carriers with 83% accuracy in individual samples, but three-way analysis for  BRCA1 ,  BRCA2 , and BRCAX had a maximum of 59% prediction accuracy. Our results suggest that, compared to  BRCA1  and  BRCA2  mutation carriers, non- BRCA1/2  (BRCAX) individuals are genetically heterogeneous. This study also demonstrates the effectiveness of RNA pools to compare the expression profiles of cell-lines from  BRCA1 ,  BRCA2 , and BRCAX cases after treatment with irradiation and mitomycin C as a method to prioritize treatment regimes for detailed downstream expression analysis.

plos genetics

Use of DNA–Damaging Agents and RNA Pooling to Assess Expression Profiles Associated with BRCA1 and BRCA2 Mutation Status in Familial Breast Cancer Patients