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.
- 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.
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