Pan-cancer analysis of CLDN18.2 shed new insights on the targeted therapy of upper gastrointestinal tract cancers

Jun Wu; Jinghua Lu; Qiuyue Chen; Haojie Chen; Yongqiang Zheng; Minggang Cheng

doi:10.3389/fphar.2024.1494131

Pan-cancer analysis of CLDN18.2 shed new insights on the targeted therapy of upper gastrointestinal tract cancers

Front Pharmacol. 2024 Nov 1:15:1494131. doi: 10.3389/fphar.2024.1494131. eCollection 2024.

Authors

Jun Wu^{1

2}, Jinghua Lu¹, Qiuyue Chen¹, Haojie Chen², Yongqiang Zheng², Minggang Cheng¹

Affiliations

¹ Department of Clinical Laboratory, People's Hospital of Bao'an District, Shenzhen Baoan Clinical Medical College of Guangdong Medical University, Shenzhen, China.
² State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.

Abstract

Background: CLDN18.2 is a widely researched drug target. However, previous research has primarily been based on immunohistochemistry results and focused on gastric cancer.

Methods: To analyze the potential cancer-targeting effect of CLDN18.2 from a multi-omics perspective, this study quantified CLDN18.2 expression in The Cancer Genome Atlas (TCGA) pan-cancer cohort. Thus, the relationships between CLDN18.2 expression and genomic alterations, immune infiltration, and prognosis were analyzed. Additionally, we performed analyses of the differentially expressed genes and enriched pathways between the high- and low-CLDN18.2 expression groups, as well as the corresponding drug sensitivity analyses.

Results: The results indicated that CLDN18.2 was highly expressed in pancreatic adenocarcinoma (PAAD), stomach adenocarcinoma (STAD), colorectal cancer (CRC), and esophageal carcinoma (ESCA). Moreover, the high- and low-CLDN18.2 expression groups presented significant differences in terms of genomic alterations and immune infiltration, such as the levels of methylation and CD4⁺ T cell infiltration. Furthermore, high CLDN18.2 expression was significantly associated with poor prognosis in bladder urothelial carcinoma (BLCA), ESCA, and PAAD. In upper gastrointestinal tract cancers (STAD, ESCA, and PAAD), downregulated gene-enriched pathways were associated with cell signaling, whereas upregulated gene-enriched pathways were associated with angiogenesis. Finally, we identified drugs associated with CLDN18.2 expression to which samples with different levels of expression were differentially sensitive.

Conclusion: CLDN18.2 was highly expressed in upper gastrointestinal tract cancers, and its expression had a significant effect on genomic alterations and the tumor microenvironment. Additionally, low CLDN18.2 expression was linked to favorable prognosis. Our study reveals the potential value of CLDN18.2 for tumor prognosis and targeted therapy in various cancers, especially upper gastrointestinal tract cancers.

Keywords: CLDN18.2; alternative splicing events; drug sensitivity; prognosis; upper gastrointestinal tract cancers.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Chih Kuang Scholarship for Outstanding Young Physician-Scientists of Sun Yat-sen University Cancer Center (CKS-SYSUCC-2024009) and the Postdoctoral Fellowship Program of CPSF (GZB20240907).