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Pathogenic germline mutations in  BRCA1  or  BRCA2  are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of  BRCA1 /2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33  BRCA1 , 22  BRCA2 , and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict  BRCA1/2  mutation status. We found that breast tumors from  BRCA1  and  BRCA2  mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of  BRCA1  tumors were basal-like while  BRCA2  tumors were mainly luminal B. Using RNA profiles, we were able to distinguish  BRCA1  tumors from sporadic tumors among basal-like tumors with 83% accuracy and  BRCA2  from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific  BRCA1/2  gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of  BRCA1/2  involvement (“BRCAness”) by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors.

Classifications within Molecular Subtypes Enables Identification of BRCA1/BRCA2 Mutation Carriers by RNA Tumor Profiling