Journal of Medical Genetics (2023): Mosaic BRCA1 promoter methylation contribution in hereditary breast/ovarian cancer pedigrees assessed using MethylDetect EpiMelt BRCA1 assay

Background: Blood-derived DNA from 20 unrelated affected cases from families with hereditary breast/ovarian cancer aggregation (lacking germline pathogenic variants in BRCA1/2, PALB2, or RAD51C/D) was screened using methylation-sensitive high-resolution melting (MS-HRM) with the MethylDetect EpiMelt BRCA1 assay targeting six CpG sites of the promoter. Pyrosequencing on blood and buccal swab samples was subsequently performed to analyze CpG methylation levels and confirm findings across positive cases and available relatives.
Key Finding: Mosaic BRCA1 promoter methylation was detected in 44% (8 of 18) of mutation-negative probands with evocative family histories (versus none of the age-matched controls), demonstrating that these de novo events frequently contribute to hereditary breast and ovarian cancer pedigrees. Furthermore, tumor analysis in methylated probands revealed frequent BRCA1 loss of heterozygosity and homologous recombination deficiency (HRD) signatures, alongside the first reported family aggregation of mosaic BRCA1 methylation across non-tumour tissues in related relatives.
Conclusion: The high prevalence of mosaic BRCA1 promoter methylation among familial breast/ovarian cancer patients lacking standard germline mutations highlights its critical role in oncogenesis and demonstrates the value of sensitive screening assays like MS-HRM for uncovering epigenetic drivers in clinical precision oncology and hereditary cancer risk evaluations.
Original Article & Authors: Published in Journal of Medical Genetics (2023), authored by Mathias Schwartz, Sabrina Ibadioune, Albain Chansavang, Sophie Vacher, Sandrine M Caputo, Hélène Delhomelle, Jennifer Wong, Khadija Abidallah, Virginie Moncoutier, Véronique Becette, Tatiana Popova, Voreak Suybeng, Antoine De Pauw, Marc-Henri Stern, Chrystelle Colas, Emmanuelle Mouret-Fourme, Dominique Stoppa-Lyonnet, Lisa Golmard, Ivan Bièche, and Julien Masliah-Planchon from the Department of Genetics, Curie Institute Hospital Group, Paris Sciences & Lettres Research University, and associated research institutions and hospitals in Paris and Saint-Cloud, France.

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