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Mosaic <i>BRCA1</i> promoter methylation contribution in hereditary breast/ovarian cancer pedigrees

Mosaic <i>BRCA1</i> promoter methylation contribution in hereditary breast/ovarian cancer pedigrees

1 mars 2024Journal of Medical Genetics

DOI : 10.1136/jmg-2023-109325

Auteurs

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 Bieche, Julien Masliah-Planchon

Résumé

Purpose

Mosaic BRCA1 promoter methylation (BRCA1meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed.

Patients

Blood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants in BRCA1/2, PALB2 or RAD51C/D, were screened by methylation-sensitive high-resolution melting. CpG analysis was performed by pyrosequencing on blood and buccal swab. Two probands carried a pathogenic variant in a moderate-penetrance gene (ATM and BARD1), and 8 of 18 others (44%) carried BRCA1meth (vs none of the 20 age-matched controls). Involvement of BRCA1 in tumourigenesis in methylated probands was demonstrated in most tested cases by detection of a loss of heterozygosity and a homologous recombination deficiency signature. Among the eight methylated probands, two had relatives with breast cancer with detectable BRCA1meth in blood, including one with high methylation levels in two non-tumour tissues.

Conclusions

The high prevalence of mosaic BRCA1meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaic BRCA1meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees.

Membres

MARC-HENRI STERN

Directeur de recherche