Abstract A049: Fallopian tubes of BRCA carriers are characterized by an alteration of epithelial differentiation

Abstract

Abstract Patients with a germline mutation in BRCA1/2 are at high risk of developing ovarian cancer, the deadliest gynecologic cancer leading to over 207,000 deaths per year in the world. Although the ovarian surface epithelium was long thought to be the origin of this cancer, it is now widely appreciated that the fallopian tube epithelium harbors the cell-of-origin for high-grade serous “ovarian” cancers (HGSC). Nonetheless the earliest stages of carcinogenesis remain poorly characterized. Our study aims to better understand why patients with highly penetrant inherited mutations in BRCA1/2 are at greater risk of HGSC using state-of-the art single cell genomics and spatial profiling of fallopian tubes removed during prophylactically risk-reducing salpingo-oophorectomies (RRSOs). Fallopian tubes from patients with BRCA1/2 mutations are fully embedded in paraffin for careful pathologic examination, limiting the technologies that can be applied to study the molecular profiles of the cancer-prone epithelium. The first aim of our study was to determine whether the samples of cells from fimbria of fallopian tubes obtained through an exfoliative cytology following RRSO are comparable to histologic preparation at the transcriptomic level. We performed single cell RNA sequencing of brushings from 14 fimbriae removed during RRSOs from high-risk mutation carriers, brushings of 3 non-carriers and 12 tissues from non-carriers. As expected, fimbrial brushing mainly consisted of epithelial cells and immune cells and were depleted of fibroblasts and endothelial cells relative to enzymatically dissociated tissue specimens. Fallopian tubes from high-risk mutation carriers were associated with signatures of altered epithelial differentiation suggesting that altered epithelial differentiation processes proceed and may even be required for cancer development. The immune compartment was also markedly different in mutation carriers compared to matched controls. We have recently described how in mutation carriers the myeloid cell compartment shifts from monocyte-enriched in normal Fallopian tubes to macrophage-enriched in HGSCs (Brand et al). In Fallopian tubes of high-risk mutation carriers, we discovered a novel subset of cancer-free patients with signatures similar to advanced tumors, suggesting myeloid compartment remodeling is a prerequisite for, although not sufficient for, tumor formation. BRCA1/2 carriers with higher macrophages also have features of dysfunctional natural killer and T cells. Ongoing spatial transcriptomic profiling of high and average risk fallopian tubes are enabling dissection of the altered cell-cell communications occurring concomitantly with disordered epithelial differentiation. Together these data are expected to advance our understanding of the cellular and molecular signatures of early stage HGSC. Leveraging this insight could lead to the development of new diagnostic tools for early detection of this cancer, an essential prerequisite for improving the chances of survival for patients. Citation Format: Quentin Chartreux, Marcela Haro, Joshua Brand, Andrew Li, Bobbie J. Rimel, Simon Gayther, Huy Dinh, Fabiola Medeiros, Kate Lawrenson. Fallopian tubes of BRCA carriers are characterized by an alteration of epithelial differentiation [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A049.