Clinical Significance of CLDN18.2 Expression in Diffuse-Type Metastatic Gastric Cancer

Background Isoform 2 of the tight junction protein claudin-18 (CLDN18.2) is a potential target of gastric cancer treatment. A treatment targeting CLDN18.2 has shown promising results in gastric cancer. We investigated the clinical significance of CLDN18.2 and other cell-adherens junction molecules (Rho GTPase-activating protein [RhoGAP] and E-cadherin) in metastatic diffuse-type gastric cancer (mDGC).Methods We evaluated CLDN18.2, RhoGAP, and E-cadherin expression by performing two-plex immunofluorescence and quantitative data analysis of H-scores of 77 consecutive mDGC patients who received first-line, platinum-based chemotherapy between March 2015 and February 2017.Results CLDN18.2 and E-cadherin expression was significantly reduced in patients with peritoneal metastasis (PM) compared with those without PM at the time of diagnosis (P=0.010 and 0.013, respectively), while it was significantly higher in patients who never exhibited PM from diagnosis to death than in those who did (p=0.001 and 0.003, respectively). Meanwhile, CLDN18.2 and E-cadherin were expressed at significantly higher levels in patients with bone metastasis than in those without it (p=0.010 and 0.001, respectively). We identified a positive correlation between the expression of CLDN18.2 and E-cadherin (p < 0.001), RhoGAP and CLDN18.2 (p=0.004), and RhoGAP and E-cadherin (p=0.001). CDLN18.2, RhoGAP, and E-cadherin expression was not associated with chemotherapy response and survival.Conclusions CLDN18.2 expression was reduced in PM but significantly intact in bone metastasis. Furthermore, a positive correlation was identified between the expression of CLDN18.2 and other adherens junction molecules, which has clinical implications for mDGC and PM pathogenesis.