Abstract
BackgroundIn 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.MethodsIn 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.ResultsWe 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.ConclusionsOur 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.
Highlights
In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1/2 patients compared to years (BRCA1) or BRCA2 cannot be identified, even though hereditary factors are expected to be involved
Median age of diagnosis was 50 years for the non-BRCA1/2 patients compared to 42 years (BRCA1) and 43.5 years (BRCA2) for mutation carriers and 61 years for sporadic cancer patients
In this report, we investigated genome-wide RNA profiles of tumors from familial breast cancer cases where no BRCA1 or BRCA2 mutations could be identified by traditional genetic analysis for germline mutations
Summary
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. Germline mutations in BRCA1 and BRCA2 only explain the breast cancer risk in approximately one fourth of these families, it is expected that additional BRCA1/2 mutations still remain undetected by the screening methods used today [2,3]. The remaining genetic susceptibility is expected to be explained by a mixture of rare high-risk variants and polygenic mechanisms involving more common and/or rare low-penetrance alleles or rare moderate penetrance genes, acting in concert to confer a high breast cancer risk [3,10,11]. A fraction of the familial aggregation of breast cancer cases may be explained by sharing of common environmental risk factors and exogenous hormone use, or be just random aggregation of sporadic breast cancers
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