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Updated: Jan 23, 2026
Establishment of Gastric Cancer Patient-derived Xenograft Models and Primary Cell Lines
Published on: July 19, 2019
Identification of candidates for driver oncogenes in scirrhous-type gastric cancer cell lines
Eirin Sai1, Yoshiyuki Miwa2, Reina Takeyama3,4
1Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Abstract:
Scirrhous-type gastric cancer (SGC) is one of the most intractable cancer subtypes in humans, and its therapeutic targets have been rarely identified to date. Exploration of somatic mutations in the SGC genome with the next-generation sequencers has been hampered by markedly increased fibrous tissues. Thus, SGC cell lines may be useful resources for searching for novel oncogenes. Here we have conducted whole exome sequencing and RNA sequencing on 2 SGC cell lines, OCUM-8 and OCUM-9. Interestingly, most of the mutations thus identified have not been reported. In OCUM-8 cells, a novel CD44-IGF1R fusion gene is discovered, the protein product of which ligates the amino-terminus of CD44 to the transmembrane and tyrosine-kinase domains of IGF1R. Furthermore, both CD44 and IGF1R are markedly amplified in the OCUM-8 genome and abundantly expressed. CD44-IGF1R has a transforming ability, and the suppression of its kinase activity leads to rapid cell death of OCUM-8. To the best of our knowledge, this is the first report describing the transforming activity of IGF1R fusion genes. However, OCUM-9 seems to possess multiple oncogenic events in its genome. In particular, a novel BORCS5-ETV6 fusion gene is identified in the OCUM-9 genome. BORCS5-ETV6 possesses oncogenic activity, and suppression of its message partially inhibits cell growth. Prevalence of these novel fusion genes among SGC awaits further investigation, but we validate the significance of cell lines as appropriate reagents for detailed genomic analyses of SGC.
Insights
Researchers identified novel fusion genes in scirrhous-type gastric cancer (SGC) cell lines. These findings highlight the potential of CD44-IGF1R and BORCS5-ETV6 as therapeutic targets for intractable SGC.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Scirrhous-type gastric cancer (SGC) presents significant therapeutic challenges due to limited identified targets.
- The fibrous nature of SGC hinders genomic mutation analysis using next-generation sequencing.
- Gastric cancer cell lines offer a valuable resource for discovering novel oncogenes.
Purpose of the Study:
- To identify novel oncogenic mutations and fusion genes in scirrhous-type gastric cancer using advanced sequencing techniques.
- To investigate the functional significance of newly discovered fusion genes in SGC pathogenesis.
- To validate the utility of SGC cell lines for comprehensive genomic analysis.
Main Methods:
- Whole exome sequencing and RNA sequencing were performed on two SGC cell lines, OCUM-8 and OCUM-9.
- Bioinformatic analysis was employed to identify somatic mutations and gene fusions.
- Functional assays were conducted to assess the oncogenic potential of identified fusion genes and their inhibition.
Main Results:
- A novel CD44-IGF1R fusion gene was discovered in OCUM-8 cells, exhibiting transforming ability. Its kinase activity suppression induced rapid cell death.
- The CD44-IGF1R fusion gene was found to be amplified and highly expressed in OCUM-8 cells.
- A novel BORCS5-ETV6 fusion gene with oncogenic activity was identified in OCUM-9 cells, partially inhibiting cell growth upon suppression.
- Most identified mutations were novel, underscoring the unique genomic landscape of these SGC cell lines.
Conclusions:
- The study reports the first transforming activity of an Insulin-like Growth Factor 1 Receptor (IGF1R) fusion gene (CD44-IGF1R).
- Novel fusion genes, CD44-IGF1R and BORCS5-ETV6, represent potential therapeutic targets for scirrhous-type gastric cancer.
- SGC cell lines are crucial tools for uncovering the complex genomic alterations driving this intractable cancer subtype.
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