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Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma
PLOS Genetics
  • Eleanor Y. Chen, Massachusetts General Hospital
  • Kimberly P. Dobrinski, Harvard Medical School
  • Kim H. Brown, Portland State University
  • Ryan Clagg, Massachusetts General Hospital
  • Elena Edelman, Brigham and Women’s Hospital
  • Myron S. Ignatius, Massachusetts General Hospital
  • Jin Yun Helen Chen, Harvard Medical School
  • Jillian Brockmann, Massachusetts General Hospital
  • G. Petur Nielsen, Massachusetts General Hospital
  • Sridhar Ramaswamy, Massachusetts General Hospital
  • Charles Keller, Oregon Health & Science University
  • Charles Lee, Harvard Medical School
  • David M. Langenau, Massachusetts General Hospital
Document Type
Article
Publication Date
8-1-2013
Subjects
  • Zebra danio -- Genetics,
  • Zabra danio -- Mitochondrial DNA -- Analysis,
  • Zebra danio -- Development
Disciplines
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.

Description

© 2013 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI
10.1371/journal.pgen.1003727
Persistent Identifier
http://archives.pdx.edu/ds/psu/18531
Citation Information
Chen EY, Dobrinski KP, Brown KH, Clagg R, Edelman E, et al. (2013) Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma. PLoS Genet 9(8): e1003727.