Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma

Eleanor Y. Chen, Kimberly P. Dobrinski, Kim H. Brown, Ryan Clagg, Elena Edelman, Myron S. Ignatius, Jin Yun Helen Chen, Jillian Brockmann, G. Petur Nielsen, Sridhar Ramaswamy, Charles Keller, Charles Lee, David M. Langenau

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth, progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization (array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS - identifying critical genes associated with tumor maintenance. Knockdown studies identified important roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation. PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS, implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of human cancer.

Original languageEnglish (US)
Article numbere1003727
JournalPLoS Genetics
Volume9
Issue number8
DOIs
StatePublished - Aug 2013

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Embryonal Rhabdomyosarcoma
comparative genomic hybridization
Comparative Genomic Hybridization
Zebrafish
Danio rerio
genomics
tumor
neoplasms
cancer
human diseases
Neoplasms
vascular endothelial growth factors
oncogenes
Oncogenes
Vascular Endothelial Growth Factor A
functional role
gene
Growth
bypass
Maintenance

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Chen, E. Y., Dobrinski, K. P., Brown, K. H., Clagg, R., Edelman, E., Ignatius, M. S., ... Langenau, D. M. (2013). Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma. PLoS Genetics, 9(8), [e1003727]. https://doi.org/10.1371/journal.pgen.1003727

Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma. / Chen, Eleanor Y.; Dobrinski, Kimberly P.; Brown, Kim H.; Clagg, Ryan; Edelman, Elena; Ignatius, Myron S.; Chen, Jin Yun Helen; Brockmann, Jillian; Nielsen, G. Petur; Ramaswamy, Sridhar; Keller, Charles; Lee, Charles; Langenau, David M.

In: PLoS Genetics, Vol. 9, No. 8, e1003727, 08.2013.

Research output: Contribution to journalArticle

Chen, EY, Dobrinski, KP, Brown, KH, Clagg, R, Edelman, E, Ignatius, MS, Chen, JYH, Brockmann, J, Nielsen, GP, Ramaswamy, S, Keller, C, Lee, C & Langenau, DM 2013, 'Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma', PLoS Genetics, vol. 9, no. 8, e1003727. https://doi.org/10.1371/journal.pgen.1003727
Chen, Eleanor Y. ; Dobrinski, Kimberly P. ; Brown, Kim H. ; Clagg, Ryan ; Edelman, Elena ; Ignatius, Myron S. ; Chen, Jin Yun Helen ; Brockmann, Jillian ; Nielsen, G. Petur ; Ramaswamy, Sridhar ; Keller, Charles ; Lee, Charles ; Langenau, David M. / Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma. In: PLoS Genetics. 2013 ; Vol. 9, No. 8.
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