Enrichment of CLDN18-ARHGAP fusion gene in gastric cancers in young adults.

Gastric cancer in young adults has been pointed out to comprise a subgroup associated with distinctive clinicopathological features, including an equal gender distribution, advanced disease and diffuse-type histology. Comprehensive molecular analyses of gastric cancers have led to molecular-based classifications and to specific and effective treatment options available. The molecular traits of gastric cancers in young adults await investigations, which should provide a clue to explore therapeutic strategies. Here we studied 146 gastric cancer patients diagnosed at the age of less than 40 years old at the Cancer Institute Hospital. Tumor specimens were examined for Helicobacter pylori infection, Epstein-Barr virus positivity, and for the expression of mismatch repair genes to indicate microsatellite instability. Overexpression, gene amplifications and rearrangements of 18 candidate driver genes were examined by immunohistochemistry and fluorescence in situ hybridization. Besides small number of cases positive for Epstein-Barr virus and microsatellite instability (n=2, each), we repeatedly found tumors having gene fusion between a tight-junction protein claudin CLDN18 and a regulator of small G proteins ARHGAP in as many as 22 cases (15.1%), and RNA sequencing identified two novel types of the fusion. Notably, patients with the CLDN18-ARHGAP fusion revealed association with aggressive disease and poor prognosis, even when grouped by their clinical stages. These observations indicate that a fusion gene between CLDN18 and ARHGAP is enriched in younger age-onset gastric cancers, and its presence may contribute to their aggressive characteristics. This article is protected by copyright. All rights reserved.