Frequent CLDN18-ARHGAP fusion in highly metastatic diffuse-type gastric cancer with relatively early onset
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Atsushi Tanaka1, Shumpei Ishikawa2, Tetsuo Ushiku1, Sho Yamazawa1, Hiroto Katoh2, Akimasa Hayashi1, Akiko Kunita1 and Masashi Fukayama1
1Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
2Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
Shumpei Ishikawa, email: [email protected]
Masashi Fukayama, email: [email protected]
Keywords: diffuse-type gastric cancer; CLDN18-ARHGAP fusion; E-cadherin; RHOA; CA9
Received: December 12, 2017 Accepted: April 28, 2018 Published: June 29, 2018
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.
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