title: Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status.
abstract: Osteosarcoma is the most common primary malignant bone tumor in children. Validated biological markers for disease prognosis available at diagnosis are lacking. No genome-wide DNA methylation studies linked to clinical outcomes have been reported in osteosarcoma to the best of our knowledge. To address this, we tested the methylome at over 1.1 million loci in 15 osteosarcoma biopsy samples obtained prior to the initiation of therapy and correlated these molecular data with disease outcomes. At more than 17% of the tested loci, samples obtained from patients who experienced disease relapse were more methylated than those from patients who did not have recurrence while patients who did not experience disease relapse had more DNA methylation at fewer than 1%. In samples from patients who went on to have recurrent disease, increased DNA methylation was found at gene bodies, intergenic regions and empirically-annotated candidate enhancers, whereas candidate gene promoters were unusual for a more balanced distribution of increased and decreased DNA methylation with 6.6% of gene promoter loci being more methylated and 2% of promoter loci being less methylated in patients with disease relapse. A locus at the TLR4 gene demonstrates one of strongest associations between DNA methylation and 5 y event-free survival (P-value = 1.7 × 10(-6)), with empirical annotation of this locus showing promoter characteristics. Our data indicate that DNA methylation information has the potential to be predictive of outcome in pediatric osteosarcoma, and that both promoters and non-promoter loci are potentially informative in DNA methylation studies.
authors.affiliation: a Division of Pediatric Hematology/Oncology; Children's Hospital at Montefiore; Albert Einstein College of Medicine ; Bronx , NY USA.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Rosenblum
authors.forename: N Ari
authors.initials: NA
authors.lastname: Wijetunga
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Fazzari
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.forename: Donald A
authors.initials: DA
authors.lastname: Barkauskas
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: COG, Children's Oncology Group; DNA methylation; EFS, event free survival; MSC, mesenchymal stem cell; PCA, principal components analysis; TLR4, Toll-like receptor 4; epigenetics; osteosarcoma; relapse