BRCA1 promoter methylation in peripheral blood is associated with the risk of triple‐negative breast cancer

Abstract

Methylation of the promoter of the BRCA1 gene in DNA derived from peripheral blood cells is a possible risk factor for breast cancer. It is not clear if this association is restricted to certain types of breast cancer or is a general phenomenon. We evaluated BRCA1 methylation status in peripheral blood cells from 942 breast cancer patients and from 500 controls. We also assessed methylation status in 262 paraffin‐embedded breast cancer tissues. Methylation status was assessed using methylation‐sensitive high‐resolution melting and was categorized as positive or negative. BRCA1 methylation in peripheral blood cells was strongly associated with the risk of triple‐negative breast cancer (TNBC) (odds ratio [OR] 4.70; 95% confidence interval [CI]: 3.13–7.07; p < 0.001), but not of estrogen‐receptor positive breast cancer (OR 0.80; 95% CI: 0.46–1.42; p = 0.46). Methylation was also overrepresented among patients with high‐grade cancers (OR 4.53; 95% CI: 2.91–7.05; p < 0.001) and medullary cancers (OR 3.08; 95% CI: 1.38–6.88; p = 0.006). Moreover, we detected a significant concordance of BRCA1 promoter methylation in peripheral blood and paired tumor tissue (p < 0.001). We found that BRCA1 promoter methylation in peripheral blood cells is associated with approximately five times greater risk of TNBC. We propose that BRCA1 methylation in blood‐derived DNA could be a novel biomarker of increased breast cancer susceptibility, in particular for triple‐negative tumors.

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

“…Although these results must be interpreted with caution as the hypermethylation levels are at the limit of detection by pyrosequencing (and thus not suitable for prediction of somatic hypermethylation), they are intriguing in the context of both possible circulating tumor DNA and findings of mosaic constitutional BRCA1 hypermethylation. Regarding the latter, mosaic constitutional BRCA1 hypermethylation has been reported in 4-7% of newborn females 40,41 as well as promoter methylation of BRCA1 or other cancer-related genes in peripheral blood in women who developed TNBC or high grade serous ovarian cancer [42][43][44][45] (see also Tang et al 46 for review). Unfortunately, a lack of corresponding fresh normal tissue hindered us from analyzing whether a mosaic methylation pattern was present also in non-malignant breast tissue.…”

Assessment of tumor suppressor promoter methylation in healthy individuals

“…While to this end constitutional epimutations of tumor suppressors have been linked to cancer risk for a few genes only [ 23 , 27 , 31 , 35 – 37 ], one may postulate that constitutional epimutations affect other tumor suppressors as well. This may have implications to our understanding of cancer risk.…”

DNA methylation of the long intergenic noncoding RNA 299 gene in triple-negative breast cancer: results from a prospective study

“…There is evidence that local hypermethylation at the BRCA1 11 , 12 gene promoter and hypermethylation at the ATM gene body 13 , 14 in PBL DNA is more frequent in breast cancer cases compared with controls. Hypermethylation of the BRCA1 promoter in PBL DNA was also associated with a greater risk of TNBC compared to other breast subtypes, indicating its application as a novel methylation biomarker of increased TNBC susceptibility 15 . In another study hypermethylation of DOK7 in whole blood DNA was proposed as a powerful epigenetic blood-based biomarker for TNBC 16 .…”