Signet ring cell carcinoma (SRCC), a subtype of gastric cancer (GC), has specific epidemiology and oncogenesis, and has poor prognosis; it still has the highest number of unmet medical needs. Cytoskeletal rearrangement and disruption of cell integrity play crucial roles in SRCC pathogenesis. Recently, many studies have been conducted on molecular alterations in SRCC; with the clarification of the clinical significance of the CLDN-ARHGAP fusion gene, a large clinical trial is underway. Herein, we examined the influence of CLDN, RhoGAP, and E-cadherin on SRCC prognosis.
We reviewed advanced 663 GC patients who received palliative chemotherapy. Of these, 135 patients (20.4%) were SRCC. Multiplexed immunofluorescence was performed on the tissue samples using antibodies against CLDN18, RhoGAP, and E-cadherin. Positivty was defined as the median value of H-score.
Overall, 85 (63%) of 135 SRCC patients, were analysed based on tissue availability. Median age at GC diagnosis was 52.5 (range 20-77) years; the female-to-male ratio was 1.2. CLDN 18 showed a strong positive correlation with E-cadherin (r = 0.705, P < 0.001). E-cadherin expression was higher in the CLDN18 positive group than in the CLDN18 negative group (mean H-score, 74.9 ± 32.3 vs. 34.0 ± 30.4, P < 0.001). RhoGAP was positively correlated with E-cadherin (r = 0.354, P = 0.002). E-cadherin expression was higher in the RhoGAP positive group than the RhoGAP negative group (mean H-score, 64.5 ± 38.7 vs. 39.1 ± 29.2, P = 0.002). Overall survival (OS) was longer in the RhoGAP-negative group than in the RhoGAP positive group (median OS, 10.8 vs 6.2 months; P = 0.014). CLDN18 and E-cadherin positivity was not associated with prognosis. However, patients with RhoGAP (-)/E-cadherin (+) showed better OS than other patients (median OS, 12.1 vs 5.6 months, P = 0.003). Multivariate analysis with Cox survival regression showed that RhoGAP was found to be an independent poor prognostic factor (p = 0.041).
The correlations among CLDN18, RhoGAP, and E-cadherin may be associated with the discohesive oncogenesis seen in SRCC. We propose that these discohesive factors may be associated with prognosis of metastatic SRCC. Further functional studies are needed to clarify the role of these molecules.
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All authors have declared no conflicts of interest.