Constitutional BRCA1 Epimutations: A Key for Understanding Basal-Like Breast and High-Grade Serous Ovarian Cancer

Area of Science:

• Genetics
• Oncology
• Epigenetics

Background:

• Germline pathogenic variants in BRCA1 and BRCA2 genes are primary causes of hereditary breast and ovarian cancers.
• BRCA1 epimutations are frequently found in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC) tissues.
• Previous studies suggested associations between BRCA1 epimutations and cancer risk, but hazard ratios were not formally assessed.

Purpose of the Study:

• To assess the hazard ratio for incident TNBC and HGSOC associated with mosaic BRCA1 epimutations in white blood cells (WBC).
• To determine the proportion of TNBC cases caused by BRCA1 epimutations.
• To investigate the timing and origin of BRCA1 epimutations.

Main Methods:

• Prospective nested case-control study within the Women's Health Initiative Study.
• Analysis of BRCA1 epimutations in WBC and matched tumor samples from TNBC patients.
• Assessment of BRCA1 epimutations in various tissues and in newborns.

Main Results:

• Mosaic WBC BRCA1 epimutations, even at low allele frequencies (<0.1%), significantly increase the risk of incident HGSOC and TNBC over 5 years.
• BRCA1 epimutations were identified as the cause of approximately 20% of TNBC cases, exceeding the rate of germline BRCA1 variants.
• Primary constitutional BRCA1 epimutations were detected across all three germ layers, present on the same allele in WBC, normal, and tumor breast tissues, suggesting an early embryonic origin.

Conclusions:

• Mosaic BRCA1 epimutations in WBC are a significant risk factor for TNBC and HGSOC.
• BRCA1 epimutations represent a substantial cause of TNBC, independent of germline mutations.
• Evidence strongly suggests BRCA1 epimutations arise from an early embryonic event with subsequent clonal expansion affecting all germ layers.