CD44-SLC1A2 Gene Fusions in Gastric Cancer

Abstract

Fusion genes are chimeric genes formed in cancers through genomic aberrations such as translocations, amplifications, and rearrangements. To identify fusion genes in gastric cancer, we analyzed regions of chromosomal imbalance in a cohort of 106 primary gastric cancers and 27 cell lines derived from gastric cancers. Multiple samples exhibited genomic breakpoints in the 5' region of SLC1A2/EAAT2, a gene encoding a glutamate transporter. Analysis of a breakpoint-positive SNU16 cell line 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. When we specifically silenced CD44-SLC1A2, cellular proliferation, invasion, and anchorage-independent growth were significantly reduced. Conversely, CD44-SLC1A2 overexpression in gastric cells stimulated these pro-oncogenic traits. CD44-SLC1A2 silencing caused significant reductions in intracellular glutamate concentrations and sensitized SNU16 cells to cisplatin, a commonly used chemotherapeutic agent in gastric cancer. We conclude that fusion of the SLC1A2 gene coding region to CD44 regulatory elements likely causes SLC1A2 transcriptional dysregulation, because tumors expressing high SLC1A2 levels also tended to be CD44-SLC1A2-positive. CD44-SLC1A2 may represent a class of gene fusions in cancers that establish a pro-oncogenic metabolic milieu favoring tumor growth and survival.

ADAR-Mediated RNA Editing Predicts Progression and Prognosis of Gastric Cancer

“…Previous molecular studies of GC have primarily focused on characterizing aberrations at the DNA level such as mutations, copy number amplifications, and fusion genes [3][4][5][6][7][8][9][10] . Alternatively, while GC gene expression studies using microarrays and RNA-sequencing have been reported, no study to date has reported a systematic analysis of RNA-edited sequence variation in primary GCs.…”

“…A heterogeneous disease arising from the complex interplay of host factors and environmental risk agents such as Helicobacter pylori, GCs have been shown to exhibit a wide spectrum of molecular aberrations 3 . At the DNA level, we and others have shown that GCs can exhibit distinct patterns of chromosomal amplifications and deletions involving oncogenes and tumor suppressor genes (ERRB2, FGFR2, and RB1), gene fusions (eg CD44-SLC1A2, CLDN18-ARHGAP26), microsatellite instability, and somatic mutations in genes such as TP53, ARID1A, and RhoA [3][4][5][6][7][8][9][10] . Clinically however, few of these molecular alterations have significantly impacted the treatment of GC patients to date, with the exceptions of traztuzumab treatment in ERBB2-positive GC, and ramucirumab (an anti-angiogenic therapy) in advanced GC 11,12 .…”

Genetics and Molecular Pathogenesis of Gastric Adenocarcinoma

“…80 The second fusion gene identified in GC was CD44-SLC1A2, which juxtaposes the SLC1A2 glutamate transporter against the CD44 promoter. 81 …”

A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing

“…We focused on detecting fusion genes since not only hematologic but also solid cancers are known to be driven by fusion genes resulting from pathogenic chromosomal translocation or inversion (Tomlins et al 2005;Wong et al 2009;Tao et al 2011;Welch et al 2011). Our approaches identified 52 fusion genes ( Fig.…”