Abstract
BackgroundHigh-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.ResultsWe 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.ConclusionsOur 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.
Highlights
High-grade soft tissue sarcomas are a heterogeneous, complex group of aggressive malignant tumors showing mesenchymal differentiation
We identified a correlation between gene expression and DNA methylation of this CpG site in Pleomorphic liposarcoma (PLS) and Dedifferentiated liposarcoma (DDLS) compared to non-neoplastic fat tissue
In the whole sarcoma collection, we identified a significant correlation between gene expression and DNA methylation of two CpG sites in the promoter of Neuronatin (NNAT)
Summary
High-grade soft tissue sarcomas are a heterogeneous, complex group of aggressive malignant tumors showing mesenchymal differentiation. Soft tissue sarcomas have increasingly been classified on the basis of underlying genetic alterations; the role of aberrant DNA methylation in these tumors is not well understood and, the usefulness of methylation-based classification is unclear. Soft tissue sarcomas (STSs) are a group of highly aggressive, histologically and genetically heterogeneous malignant tumors of mesenchymal origin. They occur almost anywhere in the human body and account for approximately 1% of all adult malignancies. Sarcomas can be classified histologically according to the soft tissue cell of origin. Undifferentiated high-grade pleomorphic sarcomas (UPSs) belong to the heterogeneous group of fibrohistiocytic tumors. Since the cellular origin of synovial sarcomas (SSs) is still unknown, these tumor belongs to sarcomas of uncertain differentiation
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