{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T15:52:32Z","timestamp":1777650752971,"version":"3.51.4"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T00:00:00Z","timestamp":1596412800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T00:00:00Z","timestamp":1596412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The tumor microenvironment (TME) plays critical roles in tumor growth and progression, however key regulators of gene expression in the TME of cutaneous malignant peripheral nerve sheath tumor (C-MPNST) and spindle cell melanoma (SCM) have not been well elucidated. Herein, we investigate the epigenetic regulation of promoters and gene bodies and their effect on the TME composition of C-MPNSTs and SCMs. A cohort of 30 patients was analyzed using differential gene expression (DGE) and gene set enrichment analysis (GSEA) using the Nanostring platform. Methylation analysis was carried out utilizing an Infinium Methylation EPIC array targeting 866,562 methylation site (CpG) islands. DGE revealed overexpression of genes related to mast cells in the TME of SCMs, and a predominance of exhausted CD8<jats:sup>+<\/jats:sup> T cells and macrophages in the TME of C-MPNSTs. Interestingly, we further observed promoter hypermethylation in key overexpressed genes and corresponding gene body hypomethylation. Analysis using ENCODE ChIP-sequencing data identified <jats:italic>CTCF<\/jats:italic> as the common transcription factor at the site of the hypomethylated probe. These findings support that the TME composition of C-MPNSTs and SCMs is at least partially independent on promoter methylation status, suggesting a possible relationship between gene body enhancers and expression of key TME genes in both entities.<\/jats:p>","DOI":"10.1038\/s41598-020-69787-1","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T10:04:58Z","timestamp":1596449098000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Correlative study of epigenetic regulation of tumor microenvironment in spindle cell melanomas and cutaneous malignant peripheral nerve sheath tumors"],"prefix":"10.1038","volume":"10","author":[{"given":"Theodore","family":"Vougiouklakis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phyu P.","family":"Aung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Varshini","family":"Vasudevaraja","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor G.","family":"Prieto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos A.","family":"Torres-Cabala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik P.","family":"Sulman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matija","family":"Snuderl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Jour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,8,3]]},"reference":[{"key":"69787_CR1","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1097\/pas.0000000000000655","volume":"40","author":"S Le Guellec","year":"2016","unstructured":"Le Guellec, S. et al. Malignant peripheral nerve sheath tumor is a challenging diagnosis: A systematic pathology review, immunohistochemistry, and molecular analysis in 160 patients From the French Sarcoma Group Database. Am. J. Surg. Pathol. 40, 896\u2013908. https:\/\/doi.org\/10.1097\/pas.0000000000000655 (2016).","journal-title":"Am. J. Surg. Pathol."},{"key":"69787_CR2","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1111\/cup.12949","volume":"44","author":"I Machado","year":"2017","unstructured":"Machado, I. et al. Desmoplastic melanoma may mimic a cutaneous peripheral nerve sheath tumor: Report of 3 challenging cases. J. Cutan. Pathol. 44, 632\u2013638. https:\/\/doi.org\/10.1111\/cup.12949 (2017).","journal-title":"J. Cutan. Pathol."},{"key":"69787_CR3","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1097\/PAT.0b013e3283631c96","volume":"45","author":"BA Wood","year":"2013","unstructured":"Wood, B. A. Desmoplastic melanoma: Recent advances and persisting challenges. Pathology 45, 453\u2013463. https:\/\/doi.org\/10.1097\/PAT.0b013e3283631c96 (2013).","journal-title":"Pathology"},{"key":"69787_CR4","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1016\/S0011-3840(96)80013-X","volume":"33","author":"JJ Lewis","year":"1996","unstructured":"Lewis, J. J. & Brennan, M. F. Soft tissue sarcomas. Curr. Probl. Surg. 33, 817\u2013872 (1996).","journal-title":"Curr. Probl. Surg."},{"key":"69787_CR5","doi-asserted-by":"publisher","first-page":"2922","DOI":"10.1002\/ijc.22239","volume":"119","author":"JR Toro","year":"2006","unstructured":"Toro, J. R. et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978\u20132001: An analysis of 26,758 cases. Int. J. Cancer 119, 2922\u20132930. https:\/\/doi.org\/10.1002\/ijc.22239 (2006).","journal-title":"Int. J. Cancer"},{"key":"69787_CR6","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1002\/1097-0142(19860515)57:10<2006::AID-CNCR2820571022>3.0.CO;2-6","volume":"57","author":"BS Ducatman","year":"1986","unstructured":"Ducatman, B. S., Scheithauer, B. W., Piepgras, D. G., Reiman, H. M. & Ilstrup, D. M. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer 57, 2006\u20132021 (1986).","journal-title":"Cancer"},{"key":"69787_CR7","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/s00401-012-0954-z","volume":"123","author":"FJ Rodriguez","year":"2012","unstructured":"Rodriguez, F. J., Folpe, A. L., Giannini, C. & Perry, A. Pathology of peripheral nerve sheath tumors: Diagnostic overview and update on selected diagnostic problems. Acta Neuropathol. 123, 295\u2013319. https:\/\/doi.org\/10.1007\/s00401-012-0954-z (2012).","journal-title":"Acta Neuropathol."},{"key":"69787_CR8","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1038\/ng.3382","volume":"47","author":"AH Shain","year":"2015","unstructured":"Shain, A. H. et al. Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. Nat. Genet. 47, 1194\u20131199. https:\/\/doi.org\/10.1038\/ng.3382 (2015).","journal-title":"Nat. Genet."},{"key":"69787_CR9","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1007\/s00280-008-0881-9","volume":"63","author":"F Mbeunkui","year":"2009","unstructured":"Mbeunkui, F. & Johann, D. J. Jr. Cancer and the tumor microenvironment: A review of an essential relationship. Cancer Chemother. Pharmacol. 63, 571\u2013582. https:\/\/doi.org\/10.1007\/s00280-008-0881-9 (2009).","journal-title":"Cancer Chemother. Pharmacol."},{"key":"69787_CR10","doi-asserted-by":"publisher","first-page":"5700","DOI":"10.1002\/jcp.27425","volume":"234","author":"M Najafi","year":"2019","unstructured":"Najafi, M. et al. Tumor microenvironment: Interactions and therapy. J. Cell. Physiol. 234, 5700\u20135721. https:\/\/doi.org\/10.1002\/jcp.27425 (2019).","journal-title":"J. Cell. Physiol."},{"key":"69787_CR11","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1002\/path.4996","volume":"244","author":"G Jour","year":"2018","unstructured":"Jour, G. et al. Novel enriched pathways in superficial malignant peripheral nerve sheath tumours and spindle\/desmoplastic melanomas. J. Pathol. 244, 97\u2013106. https:\/\/doi.org\/10.1002\/path.4996 (2018).","journal-title":"J. Pathol."},{"key":"69787_CR12","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/s41379-018-0146-z","volume":"32","author":"G Jour","year":"2019","unstructured":"Jour, G. et al. BCAT1 and miR-2504: Novel methylome signature distinguishes spindle\/desmoplastic melanoma from superficial malignant peripheral nerve sheath tumor. Modern Pathol. 32, 338\u2013345. https:\/\/doi.org\/10.1038\/s41379-018-0146-z (2019).","journal-title":"Modern Pathol."},{"key":"69787_CR13","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/nrg1655","volume":"6","author":"KD Robertson","year":"2005","unstructured":"Robertson, K. D. DNA methylation and human disease. Nat. Rev. Genet. 6, 597\u2013610. https:\/\/doi.org\/10.1038\/nrg1655 (2005).","journal-title":"Nat. Rev. Genet."},{"key":"69787_CR14","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/S1043-2760(00)00248-4","volume":"11","author":"J Newell-Price","year":"2000","unstructured":"Newell-Price, J., Clark, A. J. & King, P. DNA methylation and silencing of gene expression. Trends Endocrinol. Metab. 11, 142\u2013148 (2000).","journal-title":"Trends Endocrinol. Metab."},{"key":"69787_CR15","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1101\/gr.101907.109","volume":"20","author":"L Laurent","year":"2010","unstructured":"Laurent, L. et al. Dynamic changes in the human methylome during differentiation. Genome Res. 20, 320\u2013331. https:\/\/doi.org\/10.1101\/gr.101907.109 (2010).","journal-title":"Genome Res."},{"key":"69787_CR16","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1126\/science.6164095","volume":"211","author":"T Mohandas","year":"1981","unstructured":"Mohandas, T., Sparkes, R. S. & Shapiro, L. J. Reactivation of an inactive human X chromosome: Evidence for X inactivation by DNA methylation. Science 211, 393\u2013396. https:\/\/doi.org\/10.1126\/science.6164095 (1981).","journal-title":"Science"},{"key":"69787_CR17","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/nrc3130","volume":"11","author":"SB Baylin","year":"2011","unstructured":"Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome - biological and translational implications. Nat. Rev. Cancer 11, 726\u2013734. https:\/\/doi.org\/10.1038\/nrc3130 (2011).","journal-title":"Nat. Rev. Cancer"},{"key":"69787_CR18","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1038\/ng.2443","volume":"44","author":"M Kulis","year":"2012","unstructured":"Kulis, M. et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat. Genet. 44, 1236\u20131242. https:\/\/doi.org\/10.1038\/ng.2443 (2012).","journal-title":"Nat. Genet."},{"key":"69787_CR19","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1101\/gr.147942.112","volume":"23","author":"KE Varley","year":"2013","unstructured":"Varley, K. E. et al. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res. 23, 555\u2013567. https:\/\/doi.org\/10.1101\/gr.147942.112 (2013).","journal-title":"Genome Res."},{"key":"69787_CR20","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/nature09165","volume":"466","author":"AK Maunakea","year":"2010","unstructured":"Maunakea, A. K. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466, 253\u2013257. https:\/\/doi.org\/10.1038\/nature09165 (2010).","journal-title":"Nature"},{"key":"69787_CR21","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.ccr.2014.07.028","volume":"26","author":"X Yang","year":"2014","unstructured":"Yang, X. et al. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26, 577\u2013590. https:\/\/doi.org\/10.1016\/j.ccr.2014.07.028 (2014).","journal-title":"Cancer Cell"},{"key":"69787_CR22","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nature05916","volume":"447","author":"P Fraser","year":"2007","unstructured":"Fraser, P. & Bickmore, W. Nuclear organization of the genome and the potential for gene regulation. Nature 447, 413\u2013417. https:\/\/doi.org\/10.1038\/nature05916 (2007).","journal-title":"Nature"},{"key":"69787_CR23","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2009.06.001","volume":"137","author":"JE Phillips","year":"2009","unstructured":"Phillips, J. E. & Corces, V. G. CTCF: Master weaver of the genome. Cell 137, 1194\u20131211. https:\/\/doi.org\/10.1016\/j.cell.2009.06.001 (2009).","journal-title":"Cell"},{"key":"69787_CR24","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1101\/gad.277863.116","volume":"30","author":"R Ghirlando","year":"2016","unstructured":"Ghirlando, R. & Felsenfeld, G. CTCF: Making the right connections. Genes Dev. 30, 881\u2013891. https:\/\/doi.org\/10.1101\/gad.277863.116 (2016).","journal-title":"Genes Dev."},{"key":"69787_CR25","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1126\/science.aad9024","volume":"351","author":"D Hnisz","year":"2016","unstructured":"Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454\u20131458. https:\/\/doi.org\/10.1126\/science.aad9024 (2016).","journal-title":"Science"},{"key":"69787_CR26","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/nature16490","volume":"529","author":"WA Flavahan","year":"2016","unstructured":"Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110\u2013114. https:\/\/doi.org\/10.1038\/nature16490 (2016).","journal-title":"Nature"},{"key":"69787_CR27","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/nature10442","volume":"479","author":"S Shukla","year":"2011","unstructured":"Shukla, S. et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479, 74\u201379. https:\/\/doi.org\/10.1038\/nature10442 (2011).","journal-title":"Nature"},{"key":"69787_CR28","doi-asserted-by":"publisher","first-page":"3130","DOI":"10.1111\/jcmm.14138","volume":"23","author":"Z Shan","year":"2019","unstructured":"Shan, Z. et al. CTCF regulates the FoxO signaling pathway to affect the progression of prostate cancer. J. Cell Mol. Med. 23, 3130\u20133139. https:\/\/doi.org\/10.1111\/jcmm.14138 (2019).","journal-title":"J. Cell Mol. Med."},{"key":"69787_CR29","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1038\/nm.3909","volume":"21","author":"AJ Gentles","year":"2015","unstructured":"Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938\u2013945. https:\/\/doi.org\/10.1038\/nm.3909 (2015).","journal-title":"Nat. Med."},{"key":"69787_CR30","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nature13111","volume":"507","author":"T Bald","year":"2014","unstructured":"Bald, T. et al. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109\u2013113. https:\/\/doi.org\/10.1038\/nature13111 (2014).","journal-title":"Nature"},{"key":"69787_CR31","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/nature14282","volume":"522","author":"SB Coffelt","year":"2015","unstructured":"Coffelt, S. B. et al. IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345\u2013348. https:\/\/doi.org\/10.1038\/nature14282 (2015).","journal-title":"Nature"},{"key":"69787_CR32","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nature16140","volume":"528","author":"SK Wculek","year":"2015","unstructured":"Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413\u2013417. https:\/\/doi.org\/10.1038\/nature16140 (2015).","journal-title":"Nature"},{"key":"69787_CR33","doi-asserted-by":"publisher","first-page":"2603","DOI":"10.2217\/fon.15.176","volume":"11","author":"B Pan","year":"2015","unstructured":"Pan, B., Liao, Q., Niu, Z., Zhou, L. & Zhao, Y. Cancer-associated fibroblasts in pancreatic adenocarcinoma. Future Oncol 11, 2603\u20132610. https:\/\/doi.org\/10.2217\/fon.15.176 (2015).","journal-title":"Future Oncol"},{"key":"69787_CR34","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1126\/science.1076514","volume":"298","author":"ME Dudley","year":"2002","unstructured":"Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850\u2013854. https:\/\/doi.org\/10.1126\/science.1076514 (2002).","journal-title":"Science"},{"key":"69787_CR35","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1093\/jnci\/86.15.1159","volume":"86","author":"SA Rosenberg","year":"1994","unstructured":"Rosenberg, S. A. et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J. Natl Cancer Inst. 86, 1159\u20131166. https:\/\/doi.org\/10.1093\/jnci\/86.15.1159 (1994).","journal-title":"J. Natl Cancer Inst."},{"key":"69787_CR36","doi-asserted-by":"publisher","first-page":"25965","DOI":"10.1074\/jbc.M116.741884","volume":"291","author":"JL Johnson","year":"2016","unstructured":"Johnson, J. L. et al. Identification of neutrophil exocytosis inhibitors (Nexinhibs), small molecule inhibitors of neutrophil exocytosis and inflammation: DRUGGABILITY OF THE SMALL GTPase Rab27a. J. Biol. Chem. 291, 25965\u201325982. https:\/\/doi.org\/10.1074\/jbc.M116.741884 (2016).","journal-title":"J. Biol. Chem."},{"key":"69787_CR37","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","volume":"30","author":"MJ Aryee","year":"2014","unstructured":"Aryee, M. J. et al. Minfi: A flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30, 1363\u20131369. https:\/\/doi.org\/10.1093\/bioinformatics\/btu049 (2014).","journal-title":"Bioinformatics"},{"key":"69787_CR38","doi-asserted-by":"publisher","first-page":"3220","DOI":"10.1038\/s41467-018-05570-1","volume":"9","author":"A Chakravarthy","year":"2018","unstructured":"Chakravarthy, A. et al. Pan-cancer deconvolution of tumour composition using DNA methylation. Nat. Commun. 9, 3220. https:\/\/doi.org\/10.1038\/s41467-018-05570-1 (2018).","journal-title":"Nat. Commun."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-69787-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-69787-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-69787-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T15:35:22Z","timestamp":1670340922000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-69787-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,3]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["69787"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-69787-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,3]]},"assertion":[{"value":"30 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 August 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12996"}}