The molecular significance of methylated BRCA1 promoter in white blood cells of cancer-free females

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.

MicroRNA-126 is Dysregulated in Cancer- Free Females Harboring Methylated BRCA1 Promoter through Up-Regulation of DNMTs

“…PCR was then performed with primer specific for the S2 alternative transcript for the EGFL7 and for the DNMTs as described previously [33,34]. GAPDH mRNA was used as an internal control.…”

On metabolic reprogramming and tumor biology: A comprehensive survey of metabolism in breast cancer

“…As silencing of BRCA1 expression by means of promoter hypermethylation has also been suggested as an important event in the pathogenesis of sporadic breast cancer disease [122–124], particularly so in TNBC, these findings may have broad implications beyond hereditary breast cancer pathogenesis.…”

Integrating DNA methylation measures to improve clinical risk assessment: are we there yet? The case of BRCA1 methylation marks to improve clinical risk assessment of breast cancer

“…Associations between BRCA1 DNA methylation and breast cancer have more commonly been reported by studies that specifically examined BRCA1 promoter methylation in younger women (< 45 years) or stratified their findings by age at diagnosis. 21,22,[64][65][66] When we specifically sampled for earlyonset breast cancer cases (< 40 years), the association with BRCA1 promoter methylation and breast cancer risk is much stronger (OR 3.5, 95% CI: 1.4,10.5). 21 Wodjacz et al 67 measured BRCA1 methylation in post-menopausal women and failed to find any significant differences between cases and controls.…”

“…Cho and colleagues 68 assessed BRCA1 promoter methylation in women across a wide age range (< 45 to > 75 years old) but did not consider a sub-analysis of young women, which is particularly relevant as BRCA1 promoter methylation is more frequently detected in young women diagnosed with breast tumours and with a specific histological type. 21,66,69 If the breast cancer risk associated with BRCA1 promoter methylation mimics germline pathogenic variants (where the incidence of breast cancer in BRCA1 mutation carriers rises rapidly after the age of 30 years 70 ) the timing of DNA sampling and the case mix in terms of age and absolute risk in studies of DNA methylation will likely affect the relative risk estimates for methylation markers and breast cancer.…”