title: Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas.
abstract: Rhabdomyosarcoma is the most common soft-tissue sarcoma in children. While cytogenetic abnormalities have been well characterized in this disease, aberrant epigenetic events such as DNA hypermethylation have not been described in genome-wide studies. We have analyzed the methylation status of 25,500 promoters in normal skeletal muscle, and in cell lines and tumor samples of embryonal and alveolar rhabdomyosarcoma from pediatric patients. We identified over 1,900 CpG islands that are hypermethylated in rhabdomyosarcomas relative to skeletal muscle. Genes involved in tissue development, differentiation, and oncogenesis such as DNAJA4, HES5, IRX1, BMP8A, GATA4, GATA6, ALX3, and P4HTM were hypermethylated in both RMS cell lines and primary samples, implicating aberrant DNA methylation in the pathogenesis of rhabdomyosarcoma. Furthermore, cluster analysis revealed embryonal and alveolar subtypes had distinct DNA methylation patterns, with the alveolar subtype being enriched in DNA hypermethylation of polycomb target genes. These results suggest that DNA methylation signatures may aid in the diagnosis and risk stratification of pediatric rhabdomyosarcoma and help identify new targets for therapy.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Mahoney
authors.forename: Zizhen
authors.initials: Z
authors.lastname: Yao
authors.forename: C Chip
authors.initials: CC
authors.lastname: Keyes
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Diede
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D056426:Genetic Loci; D015894:Genome, Human; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017422:Sequence Analysis, DNA / Q000379:methods; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C485163:ALX3 protein, human; C494646:DNAJA4 protein, human; C497442:HIF1A protein, human; D050956:HSP40 Heat-Shock Proteins; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C501591:IRX1 protein, human; D014157:Transcription Factors