title: Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas.
abstract: BACKGROUND
  High-grade soft tissue sarcomas are a heterogeneous, complex group of aggressive malignant tumors showing mesenchymal differentiation. Recently, soft tissue sarcomas have increasingly been classified on the basis of underlying genetic alterations; however, the role of aberrant DNA methylation in these tumors is not well understood and, consequently, the usefulness of methylation-based classification is unclear.
  
  
  RESULTS
  We used the Infinium HumanMethylation27 platform to profile DNA methylation in 80 primary, untreated high-grade soft tissue sarcomas, representing eight relevant subtypes, two non-neoplastic fat samples and 14 representative sarcoma cell lines. The primary samples were partitioned into seven stable clusters. A classification algorithm identified 216 CpG sites, mapping to 246 genes, showing different degrees of DNA methylation between these seven groups. The differences between the clusters were best represented by a set of eight CpG sites located in the genes SPEG, NNAT, FBLN2, PYROXD2, ZNF217, COL14A1, DMRT2 and CDKN2A. By integrating DNA methylation and mRNA expression data, we identified 27 genes showing negative and three genes showing positive correlation. Compared with non-neoplastic fat, NNAT showed DNA hypomethylation and inverse gene expression in myxoid liposarcomas, and DNA hypermethylation and inverse gene expression in dedifferentiated and pleomorphic liposarcomas. Recovery of NNAT in a hypermethylated myxoid liposarcoma cell line decreased cell migration and viability.
  
  
  CONCLUSIONS
  Our analysis represents the first comprehensive integration of DNA methylation and transcriptional data in primary high-grade soft tissue sarcomas. We propose novel biomarkers and genes relevant for pathogenesis, including NNAT as a potential tumor suppressor in myxoid liposarcomas.
authors.forename: Marcus
authors.initials: M
authors.lastname: Renner
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolf
authors.forename: Hannah
authors.initials: H
authors.lastname: Meyer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.forename: Alexis
authors.initials: A
authors.lastname: Ulrich
authors.forename: Burkhard
authors.initials: B
authors.lastname: Lehner
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.forename: Esteban
authors.initials: E
authors.lastname: Czwan
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Egerer
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitt
authors.forename: Ingo
authors.initials: I
authors.lastname: Alldinger
authors.forename: Eva Kristin
authors.initials: EK
authors.lastname: Renker
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Gunhild
authors.initials: G
authors.lastname: Mechtersheimer
mesh_terms: D000465:Algorithms; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D018899:CpG Islands; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology*
chemical_list: D008565:Membrane Proteins; C490237:NNAT protein, human; D009419:Nerve Tissue Proteins