Genomic Discovery of recurrent CD44-SLC1A2 Gene Fusion in Gastric Cancer

Abstract

Among the various genomic abnormalities associated with cancers, fusion genes and transcripts are particularly notable due to their cancer-specific nature and translational potential as diagnostic and therapeutic targets. While fusion genes are well-known in haematological malignancies, our knowledge of recurrent fusion events in solid epithelial tumors is far less mature. In this study, we aimed to identify genes affected by genome rearrangements in gastric cancer (GC), which is the second highest cause of global cancer mortality. We analyzed regions of genomic imbalance in a cohort of 133 primary GCs and cell lines, and discovered several GCs exhibiting recurrent genomic breakpoints in the SLC1A2/EAAT2 glutamate transporter. 5' RACE analysis of a breakpoint-positive cell line (SNU16) revealed expression of a CD44-SLC1A2 fusion transcript, caused by a paracentric chromosomal inversion, which was predicted to produce a truncated but functional SLC1A2 protein. In primary tumors, CD44-SLC1A2 gene fusions were detected in 1 to 2% of gastric cancers, but not in adjacent matched normal gastric tissues. Functionally, CD44-SLC1A2 exhibit pro-oncogenic traits in GC which is associated with glutamate metabolism. In conclusion, our study contributes not only to the identification of a recurrent novel fusion gene candidate in GC, which contributes to GC development and plays a role in cancer metabolism, but also suggests CD44-SLC1A2 may be a potential diagnostic marker and therapeutic target in GC.