title: Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma.
abstract: Using a candidate gene approach we recently identified frequent methylation of the RASSF2 gene associated with poor overall survival in Ewing sarcoma (ES). To identify effective biomarkers in ES on a genome-wide scale, we used a functionally proven epigenetic approach, in which gene expression was induced in ES cell lines by treatment with a demethylating agent followed by hybridization onto high density gene expression microarrays. After following a strict selection criterion, 34 genes were selected for expression and methylation analysis in ES cell lines and primary ES. Eight genes (CTHRC1, DNAJA4, ECHDC2, NEFH, NPTX2, PHF11, RARRES2, TSGA14) showed methylation frequencies of>20% in ES tumors (range 24-71%), these genes were expressed in human bone marrow derived mesenchymal stem cells (hBMSC) and hypermethylation was associated with transcriptional silencing. Methylation of NPTX2 or PHF11 was associated with poorer prognosis in ES. In addition, six of the above genes also showed methylation frequency of>20% (range 36-50%) in osteosarcomas. Identification of these genes may provide insights into bone cancer tumorigenesis and development of epigenetic biomarkers for prognosis and detection of these rare tumor types.
authors.affiliation: Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alholle
authors.affiliation: Department of Biomedical, Surgical, and Dental Sciences; University of Milan; Milan, Italy; I.R.C.C.S. Istituto Ortopedico Galeazzi; Milano, Italy.
authors.forename: Anna T
authors.initials: AT
authors.lastname: Brini
authors.affiliation: Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK.
authors.forename: Seley
authors.initials: S
authors.lastname: Gharanei
authors.affiliation: Royal Orthopaedic Hospital Foundation Trust; Robert Aitken Institute of Clinical Research; University of Birmingham; Birmingham, UK.
authors.forename: Sumathi
authors.initials: S
authors.lastname: Vaiyapuri
authors.affiliation: Department of Biomedical, Surgical, and Dental Sciences; University of Milan; Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Arrigoni
authors.affiliation: Center of Excellence in Genomic Medicine Research and KACST Technology Innovation Center in Personalized Medicine; King Abdulaziz University; Jeddah, Kingdom of Saudi Arabia.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Dallol
authors.affiliation: Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK.
authors.forename: Dean
authors.initials: D
authors.lastname: Gentle
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kishida
authors.affiliation: Department of Musculoskeletal tumor surgery; Kanagawa Cancer Center; Kanagawa, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hiruma
authors.affiliation: Molecular Oncology; Felsenstein Medial Research Center; Pediatric Hematology Oncology; Schneider Children's Medical Center of Israel; Tel Aviv University; Tel Aviv, Israel.
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
authors.affiliation: Royal Orthopaedic Hospital Foundation Trust; Robert Aitken Institute of Clinical Research; University of Birmingham; Birmingham, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Grimer
authors.affiliation: Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.affiliation: Centre for Rare Diseases and Personalized Medicine; School of Clinical and Experimental Medicine; University of Birmingham; Birmingham, UK.
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D015996:Survival Rate; D059467:Transcriptome
keywords: 5-aza-2'-deoxycytidine; Ewing sarcoma; Osteosarcoma; bone tumors; functional epigenomics