Identification of a novel fusion gene HMGA2-EGFR in glioblastoma.

Abstract

Glioblastoma is one of the most malignant forms of cancer, for which no effective targeted therapy has been found. Although The Cancer Genome Atlas has provided a list of fusion genes in glioblastoma, their role in progression of glioblastoma remains largely unknown. To search for novel fusion genes, we obtained RNA-seq data from TGS-01 human glioma-initiating cells, and identified a novel fusion gene (HMGA2-EGFR), encoding a protein comprising the N-terminal region of the high-mobility group AT-hook protein 2 (HMGA2) fused to the C-terminal region of epidermal growth factor receptor (EGFR), which retained the transmembrane and kinase domains of the EGFR. This fusion gene product showed transforming potential and a high tumor-forming capacity in cell culture and in vivo. Mechanistically, HMGA2-EGFR constitutively induced a higher level of phosphorylated STAT5B than EGFRvIII, an in-frame exon deletion product of the EGFR gene that is commonly found in primary glioblastoma. Forced expression of HMGA2-EGFR enhanced orthotopic tumor formation of the U87MG human glioma cell line. Furthermore, the EGFR kinase inhibitor erlotinib blocked sphere formation of TGS-01 cells in culture and inhibited tumor formation in vivo. These findings suggest that, in addition to gene amplification and in-frame exon deletion, EGFR signaling can also be activated by gene fusion, suggesting a possible avenue for treatment of glioblastoma.

• Authors: Akiyoshi Komuro, Erna Raja, Caname Iwata, Manabu Soda, Kazunobu Isogaya, Keiko Yuki, Yasushi Ino, Masato Morikawa, Tomoki Todo, Hiroyuki Aburatani, Hiromichi Suzuki, Melissa Ranjit, Atsushi Natsume, Akitake Mukasa, Nobuhito Saito, Hitoshi Okada, Hiroyuki Mano, Kohei Miyazono, Daizo Koinuma
• Journal: International journal of cancer (Int J Cancer) Vol. 142 Issue 8 Pg. 1627-1639 (04 15 2018) ISSN: 1097-0215 [Electronic] United States
• PMID: 29193056 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 UICC.

Chemical References

• HMGA2 Protein
• HMGA2 protein, human
• Oncogene Proteins, Fusion
• EGFR protein, human
• ErbB Receptors

Topics

• Aged
• Animals
• Cell Line
• Cell Line, Tumor
• ErbB Receptors (genetics)
• Exons (genetics)
• Female
• Gene Amplification (genetics)
• Gene Deletion
• Glioblastoma (genetics)
• Glioma (genetics)
• HEK293 Cells
• HMGA2 Protein (genetics)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Oncogene Proteins, Fusion (genetics)
• Phosphorylation (genetics)
• Signal Transduction (genetics)