{"title":"Epigenomic and Transcriptomic Profiling of Solitary Fibrous Tumors Identifies Site-Specific Patterns and Candidate Genes Regulated by DNA Methylation","authors":"","doi":"10.1016/j.labinv.2024.102146","DOIUrl":null,"url":null,"abstract":"<div><div>A solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any anatomical site and is characterized by recurrent <em>NAB2::STAT6</em> fusions and metastatic progression in 10% to 30%. The cell of origin has not been identified. Despite some progress in understanding the contribution of heterogeneous fusion types and secondary mutations to SFT biology, epigenetic alterations in extrameningeal SFT remain largely unexplored, and most sarcoma research to date has focused on the use of methylation profiling for tumor classification. We interrogated genome-wide DNA methylation in 79 SFTs to identify informative epigenetic changes. RNA-seq data from targeted panels and data from the Cancer Genome Atlas (TCGA) were used for orthogonal validation of selected findings. In unsupervised clustering analysis, the top 500 most variable cytosine-guanine sites segregated SFTs by primary anatomical site. Differentially methylated genes associated with the primary SFT site included <em>EGFR</em>; <em>TBX15</em>; multiple <em>HOX</em> genes; and their cofactors <em>EBF1</em>, <em>EBF3</em>, and <em>PBX1</em>; as well as <em>RUNX1</em> and <em>MEIS1</em>. Of the 20 DMGs interrogated on the RNA-seq panel, 12 were significantly differentially expressed according to site. However, except <em>TBX15</em>, most of these also showed differential expression according to <em>NAB2::STAT6</em> fusion type, suggesting that the fusion oncogene contributes to the transcriptional regulation of these genes. Transcriptomic data confirmed an inverse correlation between gene methylation and the expression of <em>TBX15</em> in both SFT and TCGA sarcomas<em>. TBX15</em> also showed differential mRNA expression and 5′ UTR methylation between tumors in different anatomical sites in TCGA data. In all analyses, <em>TBX15</em> methylation and mRNA expression retained the strongest association with tissue of origin in SFT and other sarcomas, suggesting a possible marker to distinguish metastatic tumors from new primaries without genomic profiling. Epigenetic signatures may further help to identify SFT progenitor cells at different anatomical sites.</div></div>","PeriodicalId":17930,"journal":{"name":"Laboratory Investigation","volume":null,"pages":null},"PeriodicalIF":5.1000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Laboratory Investigation","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0023683724018245","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
A solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that can arise at any anatomical site and is characterized by recurrent NAB2::STAT6 fusions and metastatic progression in 10% to 30%. The cell of origin has not been identified. Despite some progress in understanding the contribution of heterogeneous fusion types and secondary mutations to SFT biology, epigenetic alterations in extrameningeal SFT remain largely unexplored, and most sarcoma research to date has focused on the use of methylation profiling for tumor classification. We interrogated genome-wide DNA methylation in 79 SFTs to identify informative epigenetic changes. RNA-seq data from targeted panels and data from the Cancer Genome Atlas (TCGA) were used for orthogonal validation of selected findings. In unsupervised clustering analysis, the top 500 most variable cytosine-guanine sites segregated SFTs by primary anatomical site. Differentially methylated genes associated with the primary SFT site included EGFR; TBX15; multiple HOX genes; and their cofactors EBF1, EBF3, and PBX1; as well as RUNX1 and MEIS1. Of the 20 DMGs interrogated on the RNA-seq panel, 12 were significantly differentially expressed according to site. However, except TBX15, most of these also showed differential expression according to NAB2::STAT6 fusion type, suggesting that the fusion oncogene contributes to the transcriptional regulation of these genes. Transcriptomic data confirmed an inverse correlation between gene methylation and the expression of TBX15 in both SFT and TCGA sarcomas. TBX15 also showed differential mRNA expression and 5′ UTR methylation between tumors in different anatomical sites in TCGA data. In all analyses, TBX15 methylation and mRNA expression retained the strongest association with tissue of origin in SFT and other sarcomas, suggesting a possible marker to distinguish metastatic tumors from new primaries without genomic profiling. Epigenetic signatures may further help to identify SFT progenitor cells at different anatomical sites.
期刊介绍:
Laboratory Investigation is an international journal owned by the United States and Canadian Academy of Pathology. Laboratory Investigation offers prompt publication of high-quality original research in all biomedical disciplines relating to the understanding of human disease and the application of new methods to the diagnosis of disease. Both human and experimental studies are welcome.