Abstract PR1: Genomic discovery of CD44-SLC1A2 gene fusions in gastric cancer
2010
Among the various genomic abnormalities associated with cancers,
fusion genesand transcripts are particularly notable due to their cancer-specific nature and translational potential as diagnostic and therapeutic targets. In pediatric acute lymphoblastic leukemia (ALL), assays detecting the AML-ETO and PML-RAR
fusion genesare routinely used to diagnose particular clinical subtypes, and treatment of
chronic myelogenous leukemia(CML), a disease once associated with extremely poor prognosis, has been revolutionized by imatinib, an inhibitor of the BCR-ABL
fusion gene. While
fusion genesare well- known in hematological malignancies, our knowledge of recurrent
fusionevents in solid epithelial tumors is far less mature. To date, only two
fusion geneshave been identified in solid tumors, including
TMPRSS2-ERG in prostate cancer, and EML4-ALK in non-small cell lung cancer. No recurrent
fusion geneshave been so far identified in common
gastrointestinal cancerssuch as stomach, colon and esophageal adenocarcinoma. In this study, to identify genes affected by genome rearrangements in gastric cancer (GC), which is the second highest cause of global cancer mortality, we analyzed chromosomal imbalances in a cohort of 123 primary GCs and cell lines, and discovered several tumors exhibiting recurrent genomic breakpoints in the
SLC1A2/EAAT2 glutamate transporter. 5’
RNA ligasemediated
rapid amplificationof
cDNA ends(RLM-RACE) analysis of a GC cell line with
SLC1A2breakpoints (SNU16) revealed expression of a
CD44-
SLC1A2
fusion transcript, computationally predicted to result in a truncated but functional
SLC1A2protein. In an independent tumor panel,
CD44-
SLC1A2gene
fusionswere detected in 4% to 5% of GCs (2/43), but not in adjacent matched normal gastric tissues. Using custom-designed
fusion-specific siRNAs, we show that silencing of
CD44-
SLC1A2in
fusion-positive SNU16 cells significantly reduced cellular proliferation, invasion, and colony formation, but not in cell lines lacking
CD44-
SLC1A2expression.
CD44-
SLC1A2silencing also significantly reduced intracellular glutamate levels and sensitized SNU16 cells to cisplatin.
Fusionsof
SLC1A2to upstream
CD44regulatory elements likely causes
SLC1A2transcriptional dysregulation, as tumors expressing abnormally high
SLC1A2levels also tended to be
CD44-
SLC1A2positive.
CD44-
SLC1A2gene
fusionsmay be one mechanism used by cancers to establish a pro-oncogenic metabolic milieu favoring tumor growth and survival. We believe that our study will be of great interest to the gastric cancer community, as it represents the first recurrent
fusion transcriptidentified in this disease (and for that matter any common
gastrointestinal cancer). Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR1.
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