Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution

Xuexin Yu, Wanrun Lin, Alexandra Spirtos, Yan Wang, Hao Chen, Jianfeng Ye, Jessica Parker, Ci Ci Liu, Yiying Wang, Gabriella Quinn, Feng Zhou, Setsuko K. Chambers, Cheryl Lewis, Jayanthi Lea, Bo Li, Wenxin Zheng

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Article number283
JournalBMC Medicine
Issue number1
StatePublished - Dec 2022


  • BRCA1 mutation
  • Epithelial to mesenchymal transition
  • Fallopian tube
  • High-grade serous carcinoma
  • Ovarian cancer
  • Single-cell RNA sequencing
  • T cell exhaustion

ASJC Scopus subject areas

  • General Medicine


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