High-resolution Array CGH Identifies Common Mechanisms That Drive Embryonal Rhabdomyosarcoma Pathogenesis

Genes Chromosomes Cancer. 2011 Jun;50(6):397-408. doi: 10.1002/gcc.20864. Epub 2011 Mar 15.

Abstract

Pediatric rhabdomyosarcoma occurs as two biologically distinct histological variants, embryonal (ERMS) and alveolar (ARMS). To identify genomic changes that drive ERMS pathogenesis, we used a new array comparative genomic hybridization (aCGH) platform to examine a specific subset of ERMS tumors, those occurring in children with clinically defined intermediate-risk disease. The aCGH platform used has an average probe spacing ∼1 kb, and can identify genomic changes with single gene resolution. Our data suggest that these tumors share a common genomic program that includes inactivation of a master regulator of the p53 and Rb pathways, CDKN2A/B, and activation of FGFR4, Ras, and Hedgehog (Hh) signaling. The CDKN2A/B tumor suppressor is deleted in most patient samples. FGFR4, which encodes a receptor tyrosine kinase, is activated in 20% of tumors, predominantly by amplification of mutant, activating FGFR4 alleles. Over 50% of patients had low-level gains of a region containing the Hh-pathway transcription factor GLI1, and a gene expression pattern consistent with Hh-pathway activation. We also identified intragenic deletions affecting NF1, a tumor suppressor and inhibitor of Ras, in 15% of tumor samples. Deletion of NF1 and the presence of activating Ras mutations (in 42% of patients) were mutually exclusive, suggesting NF1 loss is an alternative and potentially common mechanism of Ras activation in ERMS. Our data suggest that intermediate-risk ERMS is driven by a common set of genomic defects, a finding that has important implications for the application of targeted therapies to improve the treatment of children diagnosed with this disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Child, Preschool
  • Comparative Genomic Hybridization / methods
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Infant
  • Male
  • Neoplasm Staging
  • Neurofibromatosis 1 / genetics
  • Receptor, Fibroblast Growth Factor, Type 4 / genetics*
  • Rhabdomyosarcoma / genetics*
  • Rhabdomyosarcoma / pathology*
  • Sequence Deletion

Substances

  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 4