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

Overview

MeSH Major

  • Mutation
  • MyoD Protein
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Rhabdomyosarcoma, Embryonal

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 date

  • January 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4231202

Digital Object Identifier (DOI)

  • 10.1038/ng.2969

PubMed ID

  • 24793135

Additional Document Info

start page

  • 595

end page

  • 600

volume

  • 46

number

  • 6