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.

Recurrent Fusion of the Genes for High-mobility Group AT-hook 2 (HMGA2) and Nuclear Receptor Co-repressor 2 (NCOR2) in Osteoclastic Giant Cell-rich Tumors of Bone

“…Fusion of HMGA2 with epidermal growth factor receptor gene (EGFR) from 7p11 gives rise to a fusion gene which encodes a chimeric HMGA2-EGFR protein; this was reported in a single case of glioblastoma (71). An in-frame fusion transcript of HMGA2 with Yes1-associated transcriptional regulator gene (YAP1) from 11q22 was reported in an aggressive angiomyxoma (72).…”

“…Grep Tumorigenic properties were found for the HMGA2-LPP and HMGA2-EGFR fusion proteins, whereas functional studies have not been performed to test for effects of the HMGA2-YAP1 chimera (54,(70)(71)(72). HMGA2-LPP transforms 3T3 mouse embryonic fibroblasts (54).…”

Fusion Genes Altered in Adult Malignant Gliomas

“…A novel fusion gene HMGA2-EGFR has been identified by Komuro et al ( 23 ). It could encode a protein comprising the N-terminal region of the high-mobility group AT-hook protein 2 (HMGA2, chromosome location 12q14.3) fused to the C-terminal region of EGFR.…”

Lupeol inhibits osteosarcoma progression by up-regulation of HMGA2 via regulating miR-212-3p

“…High-mobility group AT-hook 2 (HMGA2) is a transcription factor that belongs to the non-histone chromosomal high-mobility group (HMG) protein family and is typically correlated with gene expression by remodeling the chromatin state [ 16 ]. Changes of HMGA2 have been investigated in human mesenchymal tumors, pleomorphic adenomas, and OS [ 17 ]. A previous study indicated that miR-490-3p expression was negatively correlated with HMGA2 in OS, and the tumor-suppressed function of miR-490-3p could be reversed by overexpression of HMGA2 in OS cells [ 18 ].…”