title: RASSF2 methylation is a strong prognostic marker in younger age patients with Ewing sarcoma.
abstract: Ras-association domain family of genes consist of 10 members (RASSF1-RASSF10), all containing a Ras-association (RA) domain in either the C- or the N-terminus. Several members of this gene family are frequently methylated in common sporadic cancers; however, the role of the RASSF gene family in rare types of cancers, such as bone cancer, has remained largely uninvestigated. In this report, we investigated the methylation status of RASSF1A and RASSF2 in Ewing sarcoma (ES). Quantitative real-time methylation analysis (MethyLight) demonstrated that both genes were frequently methylated in Ewing sarcoma tumors (52.5% and 42.5%, respectively) as well as in ES cell lines and gene expression was upregulated in methylated cell lines after treatment with 5-aza-2'-deoxcytidine. Overexpression of either RASSF1A or RASSF2 reduced colony formation ability of ES cells. RASSF2 methylation correlated with poor overall survival (p = 0.028) and this association was more pronounced in patients under the age of 18 y (p = 0.002). These results suggest that both RASSF1A and RASSF2 are novel epigenetically inactivated tumor suppressor genes in Ewing sarcoma and RASSF2 methylation may have prognostic implications for ES patients.
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.forename: Anna T
authors.initials: AT
authors.lastname: Brini
authors.forename: Sumathi
authors.initials: S
authors.lastname: Vaiyapuri
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alholle
authors.forename: Ashraf
authors.initials: A
authors.lastname: Dallol
authors.forename: Elena
authors.initials: E
authors.lastname: Arrigoni
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kishida
authors.forename: Toru
authors.initials: T
authors.lastname: Hiruma
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
authors.forename: Robert
authors.initials: R
authors.lastname: Grimer
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
mesh_terms: D000293:Adolescent; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000175:diagnosis* / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C411762:RASSF1 protein, human; C425300:RASSF2 protein, human; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D001374:Azacitidine
keywords: RASSF1A; RASSF2; ewing sarcoma; methylation; survival