TY - JOUR
T1 - Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution
AU - Yu, Xuexin
AU - Lin, Wanrun
AU - Spirtos, Alexandra
AU - Wang, Yan
AU - Chen, Hao
AU - Ye, Jianfeng
AU - Parker, Jessica
AU - Liu, Ci Ci
AU - Wang, Yiying
AU - Quinn, Gabriella
AU - Zhou, Feng
AU - Chambers, Setsuko K.
AU - Lewis, Cheryl
AU - Lea, Jayanthi
AU - Li, Bo
AU - Zheng, Wenxin
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - BRCA1 mutation
KW - Epithelial to mesenchymal transition
KW - Fallopian tube
KW - High-grade serous carcinoma
KW - Ovarian cancer
KW - Single-cell RNA sequencing
KW - T cell exhaustion
UR - http://www.scopus.com/inward/record.url?scp=85137558217&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85137558217&partnerID=8YFLogxK
U2 - 10.1186/s12916-022-02489-9
DO - 10.1186/s12916-022-02489-9
M3 - Article
C2 - 36076202
AN - SCOPUS:85137558217
SN - 1741-7015
VL - 20
JO - BMC medicine
JF - BMC medicine
IS - 1
M1 - 283
ER -