Congrong Liu

Identification of novel Lynch syndrome mutations in Chinese patients with endometriod endometrial cancer

Single-cell profiling reveals the intratumor heterogeneity and immunosuppressive microenvironment in cervical adenocarcinoma

Background:Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.Methods:We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.Results:Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.Conclusions:This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.Funding:Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).

The Clinicopathological and Molecular Characteristics of Endocervical Gastric-Type Adenocarcinoma and the Use of Claudin18.2 as a Potential Therapeutic Target

Endocervical gastric-type adenocarcinoma (GAS) is an aggressive type of endocervical mucinous adenocarcinoma characterized as being unrelated to human papillomavirus (HPV) and resistant to chemo/radiotherapy. In this study, we investigated the histology, immunohistochemistry patterns, and molecular characteristics in a large cohort of GAS (n = 62). Histologically, the majority of GAS cases exhibited a distinct morphology resembling gastric glands, although 2 exceptional cases exhibited HPV-associated adenocarcinoma morphology while retaining the characteristic histology of GAS at the invasive front. By immunohistochemistry, Claudin18.2 emerged as a highly sensitive and specific marker for GAS. Additionally, the strong expression of Claudin18.2 in patients with GAS indicated the potential of anti-Claudin18.2 therapy in the treatment of GAS. Other immunohistochemistry markers, including Muc6, p16, p53, Pax8, ER, and PR, may provide additional diagnostic clues for GAS. Quantitative methylation analysis revealed that the overexpression of Claudin18.2 in GAS was governed by the hypomethylation of the CLDN18.2 promoter CpG islands. To further elucidate the pathogenic mechanisms of GAS and its relationship with gastric adenocarcinoma, we performed whole exome sequencing on 11 GAS and 9 gastric adenocarcinomas. TP53, CDKN2A, STK11, and TTN emerged as the most frequently mutated genes in GAS. Mutations in these genes primarily affected cell growth, cell cycle regulation, senescence, and apoptosis. Intriguingly, these top mutated genes in GAS were also commonly mutated in gastric and pancreaticobiliary adenocarcinomas. Regarding germline variants, we identified a probably pathogenic variant in SPINK1, a gene linked to hereditary pancreatic cancer syndrome, in one GAS sample. This finding suggests a potential pathogenic link between pancreatic cancers and GAS. Overall, GAS exhibits molecular characteristics that resemble those observed in gastric and pancreaticobiliary adenocarcinomas, thereby lending support to the aggressive nature of GAS compared with HPV-associated adenocarcinoma.