Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma

Nat Commun. 2015 Jul 3;6:7557. doi: 10.1038/ncomms8557.

Abstract

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood. Here we studied 60 RMSs using whole-exome/-transcriptome sequencing, copy number (CN) and DNA methylome analyses to unravel the genetic/epigenetic basis of RMS. On the basis of methylation patterns, RMS is clustered into four distinct subtypes, which exhibits remarkable correlation with mutation/CN profiles, histological phenotypes and clinical behaviours. A1 and A2 subtypes, especially A1, largely correspond to alveolar histology with frequent PAX3/7 fusions and alterations in cell cycle regulators. In contrast, mostly showing embryonal histology, both E1 and E2 subtypes are characterized by high frequency of CN alterations and/or allelic imbalances, FGFR4/RAS/AKT pathway mutations and PTEN mutations/methylation and in E2, also by p53 inactivation. Despite the better prognosis of embryonal RMS, patients in the E2 are likely to have a poor prognosis. Our results highlight the close relationships of the methylation status and gene mutations with the biological behaviour in RMS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Cell Cycle Proteins / genetics
  • Child
  • Child, Preschool
  • DNA Methylation / genetics
  • Epigenesis, Genetic / genetics*
  • Exome
  • F-Box Proteins / genetics
  • F-Box-WD Repeat-Containing Protein 7
  • Female
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / genetics
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • Infant
  • Male
  • Mutation
  • PAX3 Transcription Factor
  • PAX7 Transcription Factor / genetics
  • PTEN Phosphohydrolase / genetics
  • Paired Box Transcription Factors / genetics
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • RNA, Messenger / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 4 / genetics
  • Repressor Proteins / genetics
  • Rhabdomyosarcoma / classification
  • Rhabdomyosarcoma / genetics
  • Rhabdomyosarcoma, Alveolar / classification
  • Rhabdomyosarcoma, Alveolar / genetics*
  • Rhabdomyosarcoma, Embryonal / classification
  • Rhabdomyosarcoma, Embryonal / genetics*
  • Transcriptome
  • Tumor Suppressor Protein p53 / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Young Adult
  • beta Catenin / genetics
  • ras Proteins / genetics

Substances

  • BCOR protein, human
  • CTNNB1 protein, human
  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • PAX3 Transcription Factor
  • PAX3 protein, human
  • PAX7 Transcription Factor
  • PAX7 protein, human
  • Paired Box Transcription Factors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Repressor Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • beta Catenin
  • Ubiquitin-Protein Ligases
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 4
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • ras Proteins

Associated data

  • GEO/GSE41263
  • GEO/GSE63891