Prevalence of BRCA1 Promoter Methylation in Cohorts of Individuals With and Without Cancer Assessed by Circulating...

BRCA1 promoter methylation (BRCA1meth) affects 20%-27% of triple-negative breast cancer (TNBC) and ovarian cancer (OvCa) and has therapeutic predictive value in both cancer types. BRCA1meth is established during early embryonic development as a constitutional event, and its detection in the peripheral blood cells of unaffected women associates with increased risk for breast cancer and OvCa. Thus, facile and sensitive assessment of BRCA1meth is an important component for both risk assessment and the therapeutic management of these cancer types.

We used the GRAIL circulating cell-free DNA (cfDNA)-based targeted methylation platform to quantify BRCA1meth in cfDNA (cfBRCA1meth) from plasma samples of individuals with and without cancer.

Detection of cfBRCA1meth was accurate and sensitive, with an empirical LoD₉₅ of 0.0081. cfBRCA1meth was found in 4.1% (113/2,790) of individuals without cancer, and it was significantly more prevalent in females compared with males (4.8% v 2.9%, P = .016), suggesting that the dynamics of BRCA1 promoter methylation and its consequences for cancer development may differ by sex. In a pan-cancer cohort comprising 2,849 patients and representing 15 tissue types, cfBRCA1meth was enriched only in TNBC (15.2%, P = .001) and OvCa (13.9%, P = .014). Importantly, in these cfBRCA1meth-positive cases, the fraction of cfBRCA1meth was correlated with a methylation-based estimate of tumor burden.

Our findings demonstrate that BRCA1meth can be robustly detected using cfDNA assessment both as a constitutional event in noncancer samples and as a metric of BRCA1meth tumor burden in individuals with BRCA1meth cancers. Therefore, the GRAIL assay provides a single quantitative platform that can be used to explore the role of BRCA1meth in cancer risk and therapeutic response.