Integrative DNA methylation and gene expression analysis in high-grade soft tissue sarcomas
- Equal contributors
1 Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
2 Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
3 Institute of Pathology, University Hospital of Cologne, 50937 Cologne, Germany
4 Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany
5 Division of Orthopedic Oncology, Department of Orthopedics, Trauma Surgery and Paraplegiology, University Hospital Heidelberg, 69118 Heidelberg, Germany
6 Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
7 Department of Hematology, Oncology, and Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany
8 Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Bioquant, University of Heidelberg, 69120 Heidelberg, Germany
Genome Biology 2013, 14:r137 doi:10.1186/gb-2013-14-12-r137Published: 17 December 2013
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.
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.
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.