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

Sep 22, 2026

Genetic predisposition plays a central role in familial breast and ovarian cancer, yet BRCA1 epimutations represent a distinct, non-genomic mechanism. This review synthesizes evidence that constitutional mosaic BRCA1 epimutations, often with extremely low allele frequencies in white blood cells, associate with substantially increased risk of incident triple-negative breast cancer and high-grade serous ovarian cancer more than five years later. Data further indicate an early embryonic clonal event spanning multiple germ layers, with epimutations occurring independently of BRCA1 promoter haplotypes but consistently on the same allele across affected individuals.

LanguageEnglish

CategoryHealthcare

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Pages11

Reading Time28 min

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Introduction

BRCA1 Epimutations in TNBC and HGSOC Tissue

Wiley Human Mutation Volume 2024, Article ID 7353984, 11 pages [https://doi.org/10.1155/2024/7353984](https://doi.org/10.1155/2024/7353984) Review Article Constitutional BRCA1 Epimutations: A Key for Understanding Basal-Like Breast and High-Grade Serous Ovarian Cancer Per E. Lønning , 1 Oleksii Nikolaienko , 1,2 and Stian Knappskog 1,2 1K. G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Oncology, Haukeland University Hospital, Bergen, Norway 2Department of Clinical Science, University of Bergen, Bergen, Norway Correspondence should be addressed to Per E. Lønning; [per.lonning@helse-bergen.no](per.lonning@helse-bergen.no) Received 14 May 2024; Accepted 8 August 2024 Academic Editor: Megan Hitchins Copyright © 2024 Per E. Lønning et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Germline pathogenic genetic variants in the BRCA1 and BRCA2 genes are the most frequent causes of familial breast and ovarian cancer. Contrasting BRCA2, epimutations in the BRCA1 gene are frequently detected in tissue from triple-negative breast (TNBC) and high-grade serous ovarian cancers (HGSOC) . While studies over the last decade have reported BRCA1 epimutations in white blood cells (WBC) from breast and ovarian cancer patients, the potential hazard ratio for incident TNBC and HGSOC was not formally assessed until recently. Conducting a prospective nested case-control study on women participating in the American Women’s Health Initiative Study, we provided ﬁrm evidence that mosaic WBC BRCA1 epimutations, even at allele frequencies < 0.1%, are associated with asigniﬁcantly increased risk of both incident HGSOC and TNBC > 5 years after WBC collection. In a second study assessing BRCA1 epimutations in WBC and matched tumor samples from TNBC, our results indicated such epimutations to be the underlying cause of around 20% of TNBC, far exceeding the percentage of cases carrying BRCA1 germline pathogenic genetic variants. We detected primary constitutional BRCA1 epimutations in tissues derived from all three germ layers. They occur independently of BRCA1 promoter haplotypes but are present on the same allele in all WBC within aﬀected individuals. Moreover, epimutations are consistently found on the same allele in normal and tumor breast tissue as well as in WBC. This ﬁnding, together with BRCA1 epimutations detected in WBC from newborns, strongly indicates an early embryonic event with clonal expansion aﬀecting all germ layers. Future work in the ﬁeld must lead to an understanding of exactly when and how the BRCA1 epimutations occur and, most importantly, whether primary constitutional epimutations in genes other than BRCA1 may cause an elevated risk of other cancer types. Keywords: BRCA1; cancer risk; constitutional; epimutations; hypermethylation; ovarian cancer; triple-negative breast cancer 1. Introduction Women harboring germline pathogenic variants (PV) in the breast cancer Type 1 susceptibility gene (BRCA1) have a lifetime risk of breast and high-grade serous ovarian cancer (HGSOC) exceeding 70% and 40%, respectively [1] . For breast cancer, the risk is particularly high for the so-called triple-negative subtype (TNBC) [2] . While the fraction of breast cancers that are TNBC varies between 10% and 20% among ethnic groups [3], about 70% of breast cancer cases arising in women harboring a PV in BRCA1 are TNBCs [4] . About 80% of all TNBCs present a basal-like gene expression signature [5–7]. Further, 40%–70% present signatures of homologous recombination repair deﬁciency (HRD) and RAD51 foci deﬁciency [8–12], similar to what is seen with BRCA1 or BRCA2 deﬁciency. However, only between 8% and 40% of all TNBCs (number pending on ethnic group) carry a germline BRCA1 PV and very few harbor BRCA2 2 Human Mutation deﬁcits as a

FAQs

What makes BRCA1 epimutations important in breast and ovarian cancer risk?

BRCA1 epimutations are frequently observed in triple-negative breast cancer and high-grade serous ovarian cancer and provide a mechanism beyond traditional BRCA1/BRCA2 genetic pathogenic variants.

How do constitutional BRCA1 epimutations relate to white blood cells and cancer development?

Mosaic BRCA1 epimutations in white blood cells, even at allele frequencies below 0.1%, are associated with increased risk of incident HGSOC and TNBC more than five years after the white blood cell sample was collected.

What do the tissue-distribution findings suggest about when epimutations occur?

Primary constitutional BRCA1 epimutations are found across tissues derived from all three germ layers and consistently on the same allele, supporting an early embryonic event with clonal expansion affecting all germ layers.

Sep 22, 2026

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