Blood cells of BRCA1 mutation and epimutation carries appear to acquire specific epigenetic signatures

Background We and others have shown that a BRCA1 epimutation detectable in blood is associated with an elevated risk of breast cancer, particularly triple-negative breast cancer, similarly as BRCA1 germline mutations. However, the effect of BRCA1 epimutation as well as germline mutations on the methylomes of carriers has not been investigated. Methods We performed a genome-wide methylation screening of blood cells from three cohorts of women: BRCA1 germline mutation carriers, BRCA1 epimutation carriers and women who were negative for both BRCA1 mutation and epimutation but had blood samples collected an average of 4.7 years prior to a breast cancer diagnosis. We then compared the methylomes of these cohorts to control individuals who were tested negative for both BRCA1 mutation and epimutation and remained cancer-free for more than eight years prior to the study. We also assessed whether methylation changes associated with BRCA1 germline mutation and epimutation were present in the tumor methylomes of TNBC cases. Results We identified specific methylation signatures in blood cells of BRCA1 mutation and epimutation carriers. These signatures were absent in the blood of cancer-free women as well as in blood samples collected years before cancer diagnosis. We subsequently linked the identified methylation changes to physiological processes and genomic regions previously implicated in breast cancer pathogenesis. Moreover, unsupervised clustering analyses confirmed the presence of identified methylation changes in the tumor methylomes of TNBC cases. Conclusions BRCA1 mutation and epimutation carriers display genome-wide methylation signatures that affect specific genomic regions and biological processes known to contribute to breast cancer pathogenesis when disrupted. Notably, these signatures are absent in the blood cells of individuals sampled years before a breast cancer diagnosis but are detectable in the tumor methylomes of TNBC, further suggesting their relevance to breast cancer development.