Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
BMC Med. 2022 Sep 9;20(1):283. doi: 10.1186/s12916-022-02489-9.
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.
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).
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.
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.
高级别浆液性癌（HGSC）是最常见和最致命的卵巢癌类型。有人提出，在携带家族性 BRCA1/2 突变的女性中，输卵管分泌细胞是卵巢 HGSC 的起源。然而，恶性转化的分子变化仍不清楚。
我们对 3 名 BRCA1 种系突变携带者（BRCA1 携带者）和 3 名无高危病史的正常对照者（非 BRCA1 携带者）的输卵管伞端进行了单细胞 RNA 和 T 细胞受体测序。
在对 19008 个细胞的转录组进行探索后，主要来自 BRCA1 样本，我们在输卵管黏膜中鉴定出 5 种主要的细胞群。与野生型 BRCA1 对照相比，BRCA1 样本的分泌细胞中存在涉及肿瘤生长和调控、趋化因子信号和抗原呈递的差异表达基因。本研究有几个新发现。首先，BRCA1 携带者的一部分输卵管分泌细胞表现出上皮-间充质转化（EMT）表型，这种表型也存在于黏膜成纤维细胞中。其次，我们发现 EMT 分泌细胞的一个以前未报道的表型分裂，具有不同的进化终点。第三，我们观察到 BRCA1 携带者的 CD8 T 细胞群体中克隆性扩张增加。在这些克隆性扩张的 CD8 T 细胞中，BRCA1 患者的输卵管黏膜中 PD-1 显著增加，表明 T 细胞耗竭可能发生在任何癌前或恶性病变发展之前。
这些结果表明，在外观正常的输卵管黏膜中 EMT 和免疫逃逸可能代表导致携带 BRCA1 种系突变的女性发生 HGSC 的早期事件。我们的研究结果提供了一个可能的分子机制，解释了为什么一些，但不是所有，携带 BRCA1 种系突变的女性会出现 HGSC 的早期发展和快速扩散。
