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Background  In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in  BRCA1  or  BRCA2  cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar underlying pathophysiological mechanisms. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for  BRCA1 / 2  germline mutations and how these subgroupings relate to different breast cancer patients within the same family.    Methods  In the current study we analyzed a collection of 70 frozen breast tumor biopsies from a total of 58 families by global RNA profiling and promoter methylation analysis.    Results  We show that distinct functional subgroupings, similar to the intrinsic molecular breast cancer subtypes, exist among non- BRCA1 / 2  breast cancers. The distribution of subtypes was markedly different from the distribution found among  BRCA1 / 2  mutation carriers. From 11 breast cancer families, breast tumor biopsies from more than one affected family member were included in the study. Notably, in 8 of these families we found that patients from the same family shared the same tumor subtype, showing a tendency of familial aggregation of tumor subtypes ( p -value = 1.7e-3). Using our previously developed  BRCA1 / 2 -signatures, we identified 7 non- BRCA1 / 2  tumors with a  BRCA1 -like molecular phenotype and provide evidence for epigenetic inactivation of  BRCA1  in three of the tumors. In addition, 7  BRCA2 -like tumors were found.    Conclusions  Our finding indicates involvement of hereditary factors in non- BRCA1 / 2  breast cancer families in which family members may carry genetic susceptibility not just to breast cancer but to a particular subtype of breast cancer. This is the first study to provide a biological link between breast cancers from family members of high-risk non- BRCA1 / 2  families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly homogeneous subtypes in order to search for new high penetrance susceptibility genes.

RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families