Frequent CLDN18-ARHGAP fusion in highly metastatic diffuse-type gastric cancer with relatively early onset

// Atsushi Tanaka 1 , Shumpei Ishikawa 2 , Tetsuo Ushiku 1 , Sho Yamazawa 1 , Hiroto Katoh 2 , Akimasa Hayashi 1 , Akiko Kunita 1 and Masashi Fukayama 1 1 Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2 Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan Correspondence to: Shumpei Ishikawa, email: sish.gpat@mri.tmd.ac.jp Masashi Fukayama, email: mfukayama-tky@umin.org Keywords: diffuse-type gastric cancer; CLDN18-ARHGAP fusion; E-cadherin; RHOA; CA9 Received: December 12, 2017     Accepted: April 28, 2018     Published: June 29, 2018 ABSTRACT CLDN18-ARHGAP26/6 fusions have been identified in gastric cancers, with a predominance in diffuse-type gastric cancers (DGCs). Although in vitro experiments have suggested an oncogenic role for CLDN18-ARHGAP26/6 fusions, the exact frequencies and clinicopathological characteristics of the fusion-positive cases are poorly understood. We analyzed 254 cases of gastric cancer (172 diffuse-type and 82 intestinal-type) using RT-PCR and FISH, and also analyzed TCGA transcriptome datasets to identify genes that are related to the aggressive behaviors of fusion-positive cancers. Our assays identified 26 fusion-positive cases, 22 of which were DGCs (22/172, 12.8%). Unlike fusion-negative DGCs, almost all fusion-positive DGCs retained E-cadherin expression (P = 0.036). Fusion-positive DGCs also showed a higher prevalence of lymphatic and distant organ metastases, and these trends were only significant in the younger age group (< 60 years). In this group, the majority of cases with distant organ metastases (4 of 6 cases) were fusion-positive, and the multivariate regression analysis revealed that fusion status was an independent predictive marker for distant organ metastases (P = 0.002). In the TCGA dataset analysis, carbonic anhydrase 9 was postulated to be a potential modulator of the age-specific effects of the fusion protein, compatible with the immunohistochemical analysis of our cohort. Therefore, CLDN18-ARHGAP26/6 fusion-positive DGCs are considered biologically distinct entities that will require more advanced therapeutic options.