Prevalence of <i>BRCA1</i> Promoter Methylation in Cohorts of Individuals With and Without Cancer Assessed by Circulating Cell-Free DNA.

Abstract

<i>BRCA1</i> promoter methylation (<i>BRCA1</i>meth) affects 20%-27% of triple-negative breast cancer (TNBC) and ovarian cancer (OvCa) and has therapeutic predictive value in both cancer types. <i>BRCA1</i>meth 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 <i>BRCA1</i>meth 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 <i>BRCA1</i>meth in cfDNA (cf<i>BRCA1</i>meth) from plasma samples of individuals with and without cancer. Detection of cf<i>BRCA1</i>meth was accurate and sensitive, with an empirical LoD₉₅ of 0.0081. cf<i>BRCA1</i>meth 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% <i>v</i> 2.9%, <i>P</i> = .016), suggesting that the dynamics of <i>BRCA1</i> 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, cf<i>BRCA1</i>meth was enriched only in TNBC (15.2%, <i>P</i> = .001) and OvCa (13.9%, <i>P</i> = .014). Importantly, in these cf<i>BRCA1</i>meth-positive cases, the fraction of cf<i>BRCA1</i>meth was correlated with a methylation-based estimate of tumor burden. Our findings demonstrate that <i>BRCA1</i>meth can be robustly detected using cfDNA assessment both as a constitutional event in noncancer samples and as a metric of <i>BRCA1</i>meth tumor burden in individuals with <i>BRCA1</i>meth cancers. Therefore, the GRAIL assay provides a single quantitative platform that can be used to explore the role of <i>BRCA1</i>meth in cancer risk and therapeutic response.