Abstract
BackgroundBRCA1 promoter methylation has been detected in DNA from peripheral blood cells of both breast cancer patients and cancer-free females. However, the pathological significance of this epigenetic change in white blood cells (WBC) remains an open question. In this study, we hypothesized that if constitutional BRCA1 methylation reflects an elevated risk for developing breast cancer (BC), WBC that harbor methylated BRCA1 in both cancer-free females and BC patients should exhibit similar molecular changes.MethodsBRCA1 promoter methylation was examined by methylation-specific PCR in WBC from 155 breast cancer patients and 143 cancer-free females. The Human Breast Cancer EpiTect Methyl II Signature PCR Array and The Human Breast Cancer RT2 Profiler™ PCR Array were used to study the methylation status and the expression profile of several breast cancer-related genes, respectively. In addition, we used label-free MS-based technique to study protein expression in plasma.ResultsWe have shown that 14.2% of BC patients and 9.1% of cancer-free females (carriers) harbored methylated BRCA1 promoter in their WBC. Interestingly, 66.7% of patients harbored methylated BRCA1 promoter in both WBC and tumors. Importantly, we have shown the presence of epigenetic changes in 9 other BC-related genes in WBC of both patients and carriers. Additionally, BRCA1 and 15 other important cancer –related genes were found to be differentially expressed in WBC from patients and carriers as compared to controls. Furthermore, we have shown that the carriers exhibited a unique plasma protein pattern different from those of BC patients and controls, with 10 proteins similarly differentially expressed in patients and carriers as compared to controls.ConclusionsThe present results suggest the presence of a strong link between aberrant methylation of the BRCA1 promoter in WBC and breast cancer –related molecular changes, which indicate the potential predisposition of the carriers for developing breast cancer. This informs the potential use of the aberrant methylation of BRCA1 promoter in WBC as a powerful non-invasive molecular marker for detecting predisposed individuals at a very early age.
Highlights
BRCA1 promoter methylation has been detected in DNA from peripheral blood cells of both breast cancer patients and cancer-free females
We provide clear evidences that females with methylated BRCA1 in their white blood cells (WBC) have, epigenetic changes, modulated gene expression profile and changes in protein expression in plasma similar to that seen in BRCA1-methylated breast cancer patients, advocating the possible involvement of BRCA1 constitutional epimutation as an alternative breast cancer predisposition mechanism
20 out of 22 were 50 years (9.1%) (Table 1). This indicates a strong association between the presence of methylated BRCA1 promoter in WBC and early onset of breast cancer (p = 0.032)
Summary
BRCA1 promoter methylation has been detected in DNA from peripheral blood cells of both breast cancer patients and cancer-free females. Errors in epigenetic regulation, which result in aberrant transcriptional silencing of a normally active gene or reactivation of a normally silent gene, are termed epimutations [2] In human cancers, this heritable yet non-genetic modification is a powerful mechanism responsible for the inhibition of different types of genes, including tumor suppressor genes [3]. The pathological features of these tumors are similar to those with inherited mutated BRCA1 Both occur at an early age and present poor histological differentiation, aneuploidy, ER and PR negativity, as well as similarities in their global gene expression profiles [11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
