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Landscape Analysis of CLDN18 Expression and Isoform Distribution in Solid Tumors: Insights From MONSTAR-SCREEN-2
Tadayoshi Hashimoto1,2, Naoko Iida1, Yoshiaki Nakamura1,2
1Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan.
Cancer Science
|June 2, 2025
Summary
Claudin 18.2 (CLDN18.2) is a promising cancer target. This study found CLDN18.2 expression in multiple solid tumors, supporting broader targeted therapy and RNA screening potential.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Claudin 18.2 (CLDN18.2) is a key protein in tight junctions and an emerging target for cancer therapy.
- While CLDN18 is studied in gastric cancer, its pan-cancer expression and isoform distribution remain largely uncharacterized.
Purpose of the Study:
- To investigate the expression profiles and isoform distribution of Claudin 18 (CLDN18) across various solid tumors.
- To evaluate CLDN18.2 as a potential pan-cancer therapeutic target and explore RNA-based screening methods.
Main Methods:
- Utilized immunohistochemistry (IHC) on 349 solid tumor samples and whole-transcriptome sequencing (WTS) on 2191 samples from the MONSTAR-SCREEN-2 study.
- Employed a splice junction analysis algorithm to characterize CLDN18 isoform distribution and analyzed paired pre- and post-chemotherapy specimens for temporal expression changes.
Main Results:
- CLDN18.2 expression (≥40% tumor cells) was detected in 16.3% of patients via IHC, notably in gastric (54.5%), biliary tract (21.7%), pancreatic (20.7%), and small intestinal (18.2%) cancers.
- WTS analysis confirmed CLDN18-high expression in 13.8% of tumors, with similar high proportions in gastric, small intestinal, pancreatic, and biliary tract cancers, showing significant correlation with IHC findings (p<0.001).
- Isoform analysis revealed a strong predominance of CLDN18.2 over CLDN18.1 (mean proportion 0.945), and longitudinal analysis of gastric cancer samples showed reduced CLDN18 expression post-chemotherapy.
Conclusions:
- CLDN18.2 is expressed in a significant subset of various solid tumors, validating its potential as a pan-cancer therapeutic target.
- Whole-transcriptome sequencing is a viable complementary method to IHC for assessing CLDN18 expression, and RNA-based screening shows promise.
- The consistent CLDN18.2 predominance supports expanding targeted therapies beyond gastric cancer and highlights the utility of RNA-based diagnostics.
