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Mosaic BRCA1 promoter methylation contribution in hereditary breast/ovarian cancer pedigrees
  1. Mathias Schwartz1,2,3,
  2. Sabrina Ibadioune1,2,
  3. Albain Chansavang1,2,
  4. Sophie Vacher1,2,
  5. Sandrine M Caputo1,2,
  6. Hélène Delhomelle1,2,
  7. Jennifer Wong1,2,
  8. Khadija Abidallah1,2,
  9. Virginie Moncoutier1,2,
  10. Véronique Becette2,4,
  11. Tatiana Popova2,5,
  12. Voreak Suybeng1,2,
  13. Antoine De Pauw1,2,
  14. Marc-Henri Stern1,2,5,
  15. Chrystelle Colas1,2,5,
  16. Emmanuelle Mouret-Fourme1,2,
  17. Dominique Stoppa-Lyonnet1,2,6,
  18. Lisa Golmard1,2,
  19. Ivan Bieche1,2,6,
  20. Julien Masliah-Planchon1,2
  1. 1 Department of genetics, Curie Institute Hospital Group, Paris, France
  2. 2 Paris Sciences & Lettres Research University, Paris, France
  3. 3 UMR3244, Curie Institute, Paris, France
  4. 4 Department of Pathology, Curie Institute, Saint-Cloud, France
  5. 5 DNA Repair and Uveal Melanoma (D.R.U.M.), Inserm U830, Curie Institute, Paris, France
  6. 6 Université de Paris Cité, Paris, France
  1. Correspondence to Dr Mathias Schwartz, Curie Institute Hospital Group, Paris, 75248 Paris cedex 05, France; mathias.schwartz{at}


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.

  • Epigenomics
  • Heredity
  • DNA Repair
  • DNA Methylation

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  • Contributors Conceptualisation—MS, SI, AC, SV, LG, IB and JM-P. Data curation—MS, SI, SV, SMC, HD, JW, KA, VM, VB, VS, ADP, CC, EM-F, IB and JM-P. Formal analysis—MS, SI, AC, SV, JW, KA, VM, VB, TP, VS, M-HS, LG, IB and JM-P. Investigation—HD, ADP, CC, EM-F and DS-L. Methodology—MS, SI, AC, SV, VB, TP, IB and JM-P. Project administration—CC, DS-L, LG, IB and JM-P. Supervision—DS-L, LG, IB and JM-P. Writing (original draft)—MS. Writing (review and editing)—SC, M-HS, LG, IB and JM-P.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.