A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations

Nat Genet. 2014 Jun;46(6):595-600. doi: 10.1038/ng.2969. Epub 2014 May 4.

Abstract

Rhabdomyosarcoma, a cancer of skeletal muscle lineage, is the most common soft-tissue sarcoma in children. Major subtypes of rhabdomyosarcoma include alveolar (ARMS) and embryonal (ERMS) tumors. Whereas ARMS tumors typically contain translocations generating PAX3-FOXO1 or PAX7-FOXO1 fusions that block terminal myogenic differentiation, no functionally comparable genetic event has been found in ERMS tumors. Here we report the discovery, through whole-exome sequencing, of a recurrent somatic mutation encoding p.Leu122Arg in the myogenic transcription factor MYOD1 in a distinct subset of ERMS tumors with poor outcomes that also often contain mutations altering PI3K-AKT pathway components. Previous mutagenesis studies had shown that MYOD1 with a p.Leu122Arg substitution can block wild-type MYOD1 function and bind to MYC consensus sequences, suggesting a possible switch from differentiation to proliferation. Our functional data now confirm this prediction. Thus, MYOD1 p.Leu122Arg defines a subset of rhabdomyosarcomas eligible for high-risk protocols and the development of targeted therapeutics.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Cell Proliferation
  • Child
  • DNA Mutational Analysis
  • Exome
  • Female
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutagenesis
  • Mutation*
  • MyoD Protein / genetics*
  • Phosphatidylinositol 3-Kinases / genetics*
  • Proto-Oncogene Proteins c-akt / genetics*
  • Rhabdomyosarcoma, Embryonal / genetics*
  • Sequence Homology, Amino Acid
  • Transcriptome
  • Young Adult

Substances

  • MyoD Protein
  • MyoD1 myogenic differentiation protein
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt