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Published on: May 14, 2019
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.
Abstract:
Claudin 18.2 (CLDN18.2), a tight junction protein isoform, is an emerging therapeutic target in oncology. CLDN18 is well-characterized in gastric cancer, but its pan-cancer expression profiles and isoform distributions are poorly documented. In the present study, we analyzed CLDN18 expression in patients with solid tumors enrolled in the MONSTAR-SCREEN-2 study using immunohistochemistry (IHC, n = 349) and whole-transcriptome sequencing (WTS, n = 2191). A splice junction analysis algorithm characterized isoform distribution patterns in WTS data and evaluated temporal changes using paired pre- and postchemotherapy specimens. IHC detected CLDN18.2 (≥ 40% of tumor cells showing any staining intensity) in 16.3% of patients, with highest prevalence in gastric (54.5%), biliary tract (21.7%), pancreatic (20.7%), and small intestinal (18.2%) cancers. WTS and IHC findings were significantly correlated (p < 0.001). WTS analysis with optimized transcript thresholds (n = 2191) demonstrated the CLDN18-high population to be 13.8%, with highest proportions in gastric (64.5%), small intestinal (40.0%), pancreatic (37.8%), and biliary tract (20.0%) cancers. Isoform analysis of 364 patients revealed CLDN18.2 predominance (mean 18.2/18.1 proportion 0.945), with CLDN18.1 predominance observed in only 4.9% of patients. Longitudinal analysis of 27 paired gastric cancer samples revealed a significant reduction in CLDN18 expression and a nonsignificant decrease in the CLDN18.2 proportion following chemotherapy. This analysis validates WTS as a complementary approach to IHC for CLDN18 assessment and demonstrates significant CLDN18 expression across multiple cancer types. The predominance of CLDN18.2 supports the expansion of targeted therapeutic approaches beyond gastric cancer and indicates the potential of RNA-based screening.
Insights
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.
