Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas

Renner, M., Wolf, T., Meyer, H., Hartmann, W., Penzel, R., Ulrich, A., Lehner, B., Hovestadt, V., Czwan, E., Egerer, G., Schmitt, T., Alldinger, I., Renker, E. K., Ehemann, V., Eils, R., Wardelmann, E., Buttner, R., Lichter, P., Brors, B., Schirmacher, P., Mechtersheimer, G. (December 2013) Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas. Genome Biol, 14 (12). r137. ISSN 1474-7596

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DOI: 10.1186/gb-2013-14-12-r137


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.

Item Type: Paper
Additional Information: 1474-760x Renner, Marcus Wolf, Thomas Meyer, Hannah Hartmann, Wolfgang Penzel, Roland Ulrich, Alexis Lehner, Burkhard Hovestadt, Volker Czwan, Esteban Egerer, Gerlinde Schmitt, Thomas Alldinger, Ingo Renker, Eva Kristin Ehemann, Volker Eils, Roland Wardelmann, Eva Buttner, Reinhard Lichter, Peter Brors, Benedikt Schirmacher, Peter Mechtersheimer, Gunhild Journal Article Research Support, Non-U.S. Gov't England Genome Biol. 2013 Dec 17;14(12):r137. doi: 10.1186/gb-2013-14-12-r137.
Uncontrolled Keywords: Algorithms Cell Line, Tumor Computational Biology/*methods CpG Islands *DNA Methylation Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Liposarcoma, Myxoid/genetics/pathology Membrane Proteins/*genetics Molecular Sequence Data Nerve Tissue Proteins/*genetics Sarcoma/*genetics/*pathology
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA methylation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > CpG islands
diseases & disorders > cancer > cancer types > sarcoma
CSHL Authors:
Communities: CSHL labs > Meyer Lab
Depositing User: Matthew Dunn
Date: 17 December 2013
Date Deposited: 25 Mar 2019 14:05
Last Modified: 25 Mar 2019 14:05
PMCID: PMC4054884
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