CD44-SLC1A2 gene fusions in gastric cancer

Jiong Tao, Nian Tao Deng, Kalpana Ramnarayanan, Baohua Huang, Hue Kian Oh, Siew Hong Leong, Seong Soo Lim, Iain Beehuat Tan, Chia Huey Ooi, Jeanie Wu, Minghui Lee, Shenli Zhang, Sun Young Rha, Hyun Cheol Chung, Duane T. Smoot, Hassan Ashktorab, Oi Lian Kon, Valere Cacheux, Celestial Yap, Nallasivam PalanisamyPatrick Tan

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish
Article number77ra30
JournalScience Translational Medicine
Volume3
Issue number77
DOIs
Publication statusPublished - 2011 Apr 6

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Gene Fusion
Stomach Neoplasms
Neoplasms
Stomach
Amino Acid Transport System X-AG
Cell Line
Growth
Cisplatin
Genes
Glutamic Acid
Cell Proliferation
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Tao, J., Deng, N. T., Ramnarayanan, K., Huang, B., Oh, H. K., Leong, S. H., ... Tan, P. (2011). CD44-SLC1A2 gene fusions in gastric cancer. Science Translational Medicine, 3(77), [77ra30]. https://doi.org/10.1126/scitranslmed.3001423
Tao, Jiong ; Deng, Nian Tao ; Ramnarayanan, Kalpana ; Huang, Baohua ; Oh, Hue Kian ; Leong, Siew Hong ; Lim, Seong Soo ; Tan, Iain Beehuat ; Ooi, Chia Huey ; Wu, Jeanie ; Lee, Minghui ; Zhang, Shenli ; Rha, Sun Young ; Chung, Hyun Cheol ; Smoot, Duane T. ; Ashktorab, Hassan ; Kon, Oi Lian ; Cacheux, Valere ; Yap, Celestial ; Palanisamy, Nallasivam ; Tan, Patrick. / CD44-SLC1A2 gene fusions in gastric cancer. In: Science Translational Medicine. 2011 ; Vol. 3, No. 77.
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Tao, J, Deng, NT, Ramnarayanan, K, Huang, B, Oh, HK, Leong, SH, Lim, SS, Tan, IB, Ooi, CH, Wu, J, Lee, M, Zhang, S, Rha, SY, Chung, HC, Smoot, DT, Ashktorab, H, Kon, OL, Cacheux, V, Yap, C, Palanisamy, N & Tan, P 2011, 'CD44-SLC1A2 gene fusions in gastric cancer', Science Translational Medicine, vol. 3, no. 77, 77ra30. https://doi.org/10.1126/scitranslmed.3001423

CD44-SLC1A2 gene fusions in gastric cancer. / Tao, Jiong; Deng, Nian Tao; Ramnarayanan, Kalpana; Huang, Baohua; Oh, Hue Kian; Leong, Siew Hong; Lim, Seong Soo; Tan, Iain Beehuat; Ooi, Chia Huey; Wu, Jeanie; Lee, Minghui; Zhang, Shenli; Rha, Sun Young; Chung, Hyun Cheol; Smoot, Duane T.; Ashktorab, Hassan; Kon, Oi Lian; Cacheux, Valere; Yap, Celestial; Palanisamy, Nallasivam; Tan, Patrick.

In: Science Translational Medicine, Vol. 3, No. 77, 77ra30, 06.04.2011.

Research output: Contribution to journalArticle

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T1 - CD44-SLC1A2 gene fusions in gastric cancer

AU - Tao, Jiong

AU - Deng, Nian Tao

AU - Ramnarayanan, Kalpana

AU - Huang, Baohua

AU - Oh, Hue Kian

AU - Leong, Siew Hong

AU - Lim, Seong Soo

AU - Tan, Iain Beehuat

AU - Ooi, Chia Huey

AU - Wu, Jeanie

AU - Lee, Minghui

AU - Zhang, Shenli

AU - Rha, Sun Young

AU - Chung, Hyun Cheol

AU - Smoot, Duane T.

AU - Ashktorab, Hassan

AU - Kon, Oi Lian

AU - Cacheux, Valere

AU - Yap, Celestial

AU - Palanisamy, Nallasivam

AU - Tan, Patrick

PY - 2011/4/6

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N2 - 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.

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Tao J, Deng NT, Ramnarayanan K, Huang B, Oh HK, Leong SH et al. CD44-SLC1A2 gene fusions in gastric cancer. Science Translational Medicine. 2011 Apr 6;3(77). 77ra30. https://doi.org/10.1126/scitranslmed.3001423