Background
High-grade serous carcinoma (HGSC) is the most frequent and lethal type of ovarian cancer. It has been proposed that tubal secretory cells are the origin of ovarian HGSC in women with familial BRCA1/2 mutations. However, the molecular changes underlying malignant transformation remain unknown.
Method
We performed single-cell RNA and T cell receptor sequencing of tubal fimbriated ends from 3 BRCA1 germline mutation carriers (BRCA1 carriers) and 3 normal controls with no high-risk history (non-BRCA1 carriers).
Results
Exploring the transcriptomes of 19,008 cells, predominantly from BRCA1+ samples, we identified 5 major cell populations in the fallopian tubal mucosae. The secretory cells of BRCA1+ samples had differentially expressed genes involved in tumor growth and regulation, chemokine signaling, and antigen presentation compared to the wild-type BRCA1 controls. There are several novel findings in this study. First, a subset of the fallopian tubal secretory cells from one BRCA1 carrier exhibited an epithelial-to-mesenchymal transition (EMT) phenotype, which was also present in the mucosal fibroblasts. Second, we identified a previously unreported phenotypic split of the EMT secretory cells with distinct evolutionary endpoints. Third, we observed increased clonal expansion among the CD8+ T cell population from BRCA1+ carriers. Among those clonally expanded CD8+ T cells, PD-1 was significantly increased in tubal mucosae of BRCA1+ patients compared with that of normal controls, indicating that T cell exhaustion may occur before the development of any premalignant or malignant lesions.
Conclusion
These results indicate that EMT and immune evasion in normal-looking tubal mucosae may represent early events leading to the development of HGSC in women with BRCA1 germline mutation. Our findings provide a probable molecular mechanism explaining why some, but not all, women with BRCA1 germline mutation present with early development and rapid dissemination of HGSC.
Highlights
The majority of respondents evaluate lymph nodes via sentinel lymph node mapping for grade 1–2 endometrial cancer.
Only 50% of respondents perform intraoperative sentinel lymph node mapping for grade 3 endometrial cancer.
90% of respondents give chemotherapy-based adjuvant treatment for advanced endometrial cancer.
75% of respondents combine radiation therapy with chemotherapy in stage III endometrial cancer.
Metabolomics is the global analysis of metabolites within various tissues and biological fluids. The metabolome more closely represents the phenotype than the genome or proteome as metabolite fluxes are a product of both genetic and environmental influences. Thus, metabolomics may provide insight into the nutritional, metabolic, and general health status during different stages of the life cycle and during pathological conditions. The workflow is as follows: formulate hypothesis ‐ design study ‐ collect samples ‐ prepare and analyze samples to identify compounds ‐ analyze data ‐ evaluate hypothesis and generate hypotheses ‐ apply to patient care. Although experts in each area of the workflow are needed, at least one team member must provide continuity from formulation of hypotheses to patient care. We are testing the hypotheses that the plasma carnitinome will change in piglets between days 2 through 8 of life, in young healthy adults before and after being placed on a trial ketogenic diet, and in patients with epilepsy when treated with ketogenic therapy. The long term goal is to more effectively and efficiently translate research concerning changes in the carnitinome and metabolome into practical solutions for patients with various pathological conditions. This continuity and integration of knowledge from basic science to the clinic will accelerate research from discovery to improved patient care.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.