Document Type
Article
Publication Date
3-1-2026
Original Citation
Liu E,
Antonio M,
Nance T,
Menghi F.
Prevalence of JCO Precis Oncol. 2026;10(3):e2500854.
Keywords
JGM, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Young Adult, Case-Control Studies, Cell-Free Nucleic Acids, DNA Methylation, Genes, BRCA1, Ovarian Neoplasms, Promoter Regions, Genetic, Triple Negative Breast Neoplasms
JAX Source
JCO Precis Oncol. 2026;10(3):e2500854.
ISSN
2473-4284
PMID
41802188
DOI
https://doi.org/10.1200/PO-25-00854
Grant
Supported by NCI grants P30CA034196 and R01CA255705 (to E.T.L.).
Abstract
PURPOSE: 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.
METHODS: We used the GRAIL circulating cell-free DNA (cfDNA)–based targeted meth- ylation platform to quantify BRCA1meth in cfDNA (cfBRCA1meth) from plasma samples of individuals with and without cancer.
RESULTS: 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 5 .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 5 .001) and OvCa (13.9%, P 5 .014). Im- portantly, in these cfBRCA1meth-positive cases, the fraction of cfBRCA1meth was correlated with a methylation-based estimate of tumor burden.
CONCLUSION: 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
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