• Background: The study assessed the prevalence of constitutional BRCA1 promoter hypermethylation (epimutations) in blood cells using specific Methylation-Sensitive High-Resolution Melting (MS-HRM) EpiMelt assays from Methyl Detect ApS (Aalborg, Denmark) targeting six CpG sites of the core BRCA1 promoter. The cohort comprised 112 early-onset (≤ 30 years) triple-negative breast cancer (TNBC) patients without cancer-predisposing pathogenic variants (PVs), compared against 87 early-onset TNBC patients carrying PVs and 93 late-onset (≥ 70 years) TNBC patients without PVs.

• Key Finding: A significantly higher prevalence of constitutional BRCA1 epimutations was observed in early-onset TNBC patients without PVs (33.9%) compared to early-onset patients with PVs (1.1%, p < 0.001) and late-onset patients (11.8%, p < 0.001). These elevated differences remained statistically significant even when analyses were restricted to low variant epiallele frequencies (VEF under 1%).

• Conclusion: Constitutional BRCA1 epimutations play a major role in early-onset TNBC risk, demonstrating that even low-VEF epimutations detected by high-sensitivity assays impact susceptibility and should be integrated into multifactorial models for personalized breast cancer risk.

• Original Article & Authors: Published in Clinical Epigenetics (2025) by lead and corresponding author Mathias Schwartz alongside co-authors Sabrina Ibadioune, Hélène Delhomelle, Solenn Barraud, Sandrine M. Caputo, Olfa Trabelsi-Grati, Marie-Charlotte Villy, Anthony Laugé, Roseline Tang, Etienne Rouleau, Emmanuelle Mouret-Fourme, Dominique Stoppa-Lyonnet, Éric Pasmant, Lisa Golmard, Chrystelle Colas, and Ivan Bièche from the Department of Genetics at Curie Institute, Paris Sciences and Lettres (PSL) University, and Gustave-Roussy Cancer Campus in France.

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