CD44-SLC1A2 Gene Fusions in Gastric Cancer

One partner of a fusion gene found in gastric cancer, CD44-SLC1A2, may contribute to the tumor’s abnormal metabolism. Bad Drivers Steer Scientists Toward New Drug Targets It’s ironic, but cancer cells are notoriously bad at cell division, losing bits and rearranging chunks of the genome in the process. One result of this chaos is the birth of chimeric genes, wherein one gene segment gets erroneously fused to part of another, sometimes forming peculiar hybrid proteins that contribute to the cancer cell phenotype. For example, the fused aberrant BCR-ABL gene drives chronic myelogenous leukemia and has proven to be a vulnerable target for therapy. Gene fusions in solid cancers are not so easy to spot, but have been located in prostate and small cell lung cancers. Now, Tao and her co-workers have documented a fusion gene that forms in a small percentage of gastric tumor cells and may contribute to the development of cancer. The authors analyzed copy number variations of genes in more than 100 primary gastric tumors and 27 established gastric tumor cell lines and pinpointed a common breakpoint in three and one, respectively. The resulting chimeric gene fused most of the coding region of SLC1A2/EAAT2 (which encodes a glutamate transporter) to what is probably the strong transcriptional promoter of its neighboring gene, CD44, likely the result of a chromosome inversion. The fusion gene generated a truncated SLC1A2 protein in the original tumors and in a new group of gastric cancers created by the authors through overexpression of the fusion gene in normal gastric cells. But an abnormal protein that lives in tumor cells can be an innocent bystander. So, the authors asked whether the truncated SLC1A2 contributes to gastric cancer development, and their evidence suggested that the answer is yes. Cells in which shortened SLC1A2 expression was silenced with small interfering RNA were less proficient at dividing and invading soft substrates—hallmarks of cancer cells—and overexpression of the pruned protein enhanced these traits. Consistent with the function of SLC1A2 as a transporter of glutamate, the amino acid—which can act as a growth regulator—existed in higher concentrations in gastric cancer cells and cell lines than in normal cells. And in a final set of incriminating evidence, tumor cells that sported the CD44-SLC1A2 fusion gene had higher amounts of SLC1A2 than did wild-type cells, suggesting that this aberrant protein may trigger a pro-oncogenic phenotype. Most other genes that are fused in cancers encode kinase enzymes or transcriptional regulatory proteins. The implication of an overexpressed metabolism-related gene in some gastric tumors may define a new class of cancer-driving genes, although the protein could also augment other cancer-promoting genetic aberrations. The utility of this fusion gene as a drug target or prognostic tool will require more studies, but this particular mistake made by a dividing cancer cell may act as a GPS that directs researchers down a new therapeutic avenue for gastric cancer. 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.