Abstract Germline mutations in BRCA1 and BRCA2 dramatically increase the lifetime risk of developing both ovarian and breast cancers. While the fallopian tube epithelium has been recognized as the likely cell of origin for high-grade serous carcinoma (HGSC), the molecular mechanisms that initiate malignant transformation in BRCA1/2-associated tissues—whether in the fallopian tube or the breast—remain poorly defined. Understanding these early events is critical to identify shared pathways that predispose BRCA mutation carriers to cancer. To address this, we applied single-cell transcriptomic and epigenomic profiling to fallopian tube samples from BRCA1/2 mutation carriers undergoing prophylactic risk-reducing salpingo-oophorectomy (RRSO), aiming to uncover early cellular and molecular alterations that may also inform early breast tumorigenesis.We compared the cellular and transcriptomic landscapes of fimbrial epithelial brushings obtained via exfoliative cytology with those from conventional tissue specimens. Single-cell RNA sequencing was performed on 14 fimbrial brushings from high-risk BRCA1/2 mutation carriers, 3 brushings from non-carriers, and 12 tissue samples from non-carriers. In parallel, single-cell multi-omic analyses were conducted on short-term epithelial cultures derived from 4 high-risk and 2 average-risk individuals. This design enabled a high-resolution assessment of epithelial heterogeneity, transcriptional states, and gene regulatory differences between BRCA mutation carriers and controls.Fimbrial brushings primarily contained epithelial and immune populations, with a relative depletion of fibroblasts and endothelial cells compared to tissue samples, allowing detailed analysis of epithelial biology. Cells from BRCA mutation carriers exhibited marked transcriptomic alterations, including disrupted epithelial differentiation trajectories and upregulation of genes involved in mitochondrial respiration and oxidative phosphorylation. These findings suggest early mitochondrial and metabolic remodeling that may precede malignant transformation. In addition, transcriptional remodeling of immune-related pathways indicated subtle immunologic changes in the local microenvironment that could contribute to a permissive state for tumor initiation.By uncovering early transcriptomic and metabolic reprogramming in BRCA-mutated epithelia, this work provides new insights into the biological underpinnings of hereditary cancer predisposition. The identification of early molecular alterations in BRCA mutation carriers may inform the development of biomarkers and preventive strategies relevant to both ovarian and breast cancer, ultimately advancing risk prediction and early detection efforts. Citation Format: Q. Chartreux, M. Haro, J. Brand, A. Li, B. J. Rimel, S. Gayther, H. Dinh, F. Madeiros, K. Lawrenson. Disrupted epithelial differentiation and mitochondrial remodeling as early events in BRCA-associated carcinogenesis abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-13-07.
Chartreux et al. (Tue,) studied this question.