{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:33:54Z","timestamp":1792100034579,"version":"4.4.0"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T00:00:00Z","timestamp":1617840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker.<\/jats:p>","DOI":"10.3390\/ijms22083845","type":"journal-article","created":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T11:58:45Z","timestamp":1617883125000},"page":"3845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System"],"prefix":"10.3390","volume":"22","author":[{"given":"Sarah","family":"Teuber-Hanselmann","sequence":"first","affiliation":[{"name":"Institute of Neuropathology, University Hospital Essen, D-45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Worm","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, D-45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Macha","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital Essen, D-45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8063-9765","authenticated-orcid":false,"given":"Andreas","family":"Junker","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital Essen, D-45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,8]]},"reference":[{"key":"ref_1","first-page":"179","article-title":"O(6)-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: Enzyme activity, promoter methylation and immunohistochemistry","volume":"1816","author":"Christmann","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11209","DOI":"10.1007\/s13277-016-4994-1","article-title":"DNA methylation and histone acetylation regulate the expression of MGMT and chemosensitivity to temozolomide in malignant melanoma cell lines","volume":"37","author":"Chen","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4186","DOI":"10.1038\/srep04186","article-title":"A critical re-assessment of DNA repair gene promoter methylation in non-small cell lung carcinoma","volume":"4","author":"Do","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Gu, C., Lu, J., Cui, T., Lu, C., Shi, H., Xu, W., Yuan, X., Yang, X., Huang, Y., and Lu, M. (2013). Association between MGMT promoter methylation and non-small cell lung cancer: A meta-analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072633"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.11613\/BM.2015.017","article-title":"Aberrant methylation patterns in cancer: A clinical view","volume":"25","author":"Paska","year":"2015","journal-title":"Biochem. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1056\/NEJMoa043331","article-title":"MGMT gene silencing and benefit from temozolomide in glioblastoma","volume":"352","author":"Hegi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/ijc.20575","article-title":"Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors","volume":"113","author":"Mollemann","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_8","first-page":"4812","article-title":"Differential expression of drug resistance genes and chemosensitivity in glial cell lineages correlate with differential response of oligodendrogliomas and astrocytomas to chemotherapy","volume":"60","author":"Nutt","year":"2000","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/nature10860","article-title":"IDH mutation impairs histone demethylation and results in a block to cell differentiation","volume":"483","author":"Lu","year":"2012","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ccr.2010.12.014","article-title":"Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases","volume":"19","author":"Xu","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.ccr.2010.03.017","article-title":"Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma","volume":"17","author":"Noushmehr","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s11060-014-1663-3","article-title":"MGMT promoter methylation in non-neoplastic brain","volume":"121","author":"Hsu","year":"2015","journal-title":"J. Neurooncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1016\/S0002-9440(10)63511-0","article-title":"Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation","volume":"163","author":"Kang","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1007\/s00428-003-0877-0","article-title":"The promoter methylation status of the DNA repair gene O6-methylguanine-DNA methyltransferase in ulcerative colitis","volume":"443","author":"Matsumura","year":"2003","journal-title":"Virchows Arch."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/S1665-2681(19)31251-7","article-title":"Promotor methylation: Does it affect response to therapy in chronic hepatitis C (G4) or fibrosis?","volume":"13","author":"Zekri","year":"2014","journal-title":"Ann. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1158\/1078-0432.CCR-05-1601","article-title":"CpG island methylation status in gastric carcinoma with and without infection of Epstein-Barr virus","volume":"12","author":"Chang","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s13402-015-0242-8","article-title":"DNA methylation patterns in EBV-positive and EBV-negative Hodgkin lymphomas","volume":"38","author":"Dhiab","year":"2015","journal-title":"Cell. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1002\/ijc.22849","article-title":"Differential DNA methylation associated with hepatitis B virus infection in hepatocellular carcinoma","volume":"121","author":"Su","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/bpa.12800","article-title":"MicroRNA profiles of MS gray matter lesions identify modulators of the synaptic protein synaptotagmin-7","volume":"30","author":"Fritsche","year":"2020","journal-title":"Brain Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1002\/glia.23784","article-title":"DNA methylation in Schwann cells and in oligodendrocytes","volume":"68","author":"Moyon","year":"2020","journal-title":"Glia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.celrep.2013.12.031","article-title":"Regulation of TET protein stability by calpains","volume":"6","author":"Wang","year":"2014","journal-title":"Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s00401-006-0045-0","article-title":"Protein co-expression with axonal injury in multiple sclerosis plaques","volume":"111","author":"Williams","year":"2006","journal-title":"Acta Neuropathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1097\/NEN.0b013e31829c7370","article-title":"Calcium influx and calpain activation mediate preclinical retinal neurodegeneration in autoimmune optic neuritis","volume":"72","author":"Hoffmann","year":"2013","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S0006-8993(97)01381-4","article-title":"Increased calpain expression in experimental demyelinating optic neuritis: An immunocytochemical study","volume":"784","author":"Shields","year":"1998","journal-title":"Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5768","DOI":"10.1073\/pnas.95.10.5768","article-title":"Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis","volume":"95","author":"Shields","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.7314\/APJCP.2015.16.5.1945","article-title":"MGMT-B gene promoter hypermethylation in patients with inflammatory bowel disease\u2014A novel finding","volume":"16","author":"Mokarram","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.3389\/fgene.2019.01150","article-title":"DNA Methylation Cancer Biomarkers: Translation to the Clinic","volume":"10","author":"Locke","year":"2019","journal-title":"Front. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.mad.2016.04.003","article-title":"Methylation analysis of DNA repair genes in Alzheimer\u2019s disease","volume":"161","author":"Coppede","year":"2017","journal-title":"Mech. Ageing Dev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.3748\/wjg.v19.i20.3043","article-title":"MGMT and MLH1 methylation in Helicobacter pylori-infected children and adults","volume":"19","author":"Alvarez","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jare.2012.11.002","article-title":"Methylation of multiple genes in hepatitis C virus associated hepatocellular carcinoma","volume":"5","author":"Zekri","year":"2014","journal-title":"J. Adv. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/1746-1596-7-87","article-title":"Analysis of aberrant methylation on promoter sequences of tumor suppressor genes and total DNA in sputum samples: A promising tool for early detection of COPD and lung cancer in smokers","volume":"7","author":"Guzman","year":"2012","journal-title":"Diagn. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/S1470-2045(14)70379-1","article-title":"Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): A multicentre, randomised, open-label, phase 3 trial","volume":"15","author":"Stupp","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"571","DOI":"10.3233\/JAD-2012-111223","article-title":"Genome-wide DNA methylation differences between late-onset Alzheimer\u2019s disease and cognitively normal controls in human frontal cortex","volume":"29","author":"Bakulski","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/nbt.2487","article-title":"Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis","volume":"31","author":"Liu","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9788","DOI":"10.18632\/oncotarget.7125","article-title":"Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFkappaB pathway in gastric cancer development","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"a001651","DOI":"10.1101\/cshperspect.a001651","article-title":"The nuclear factor NF-kappaB pathway in inflammation","volume":"1","author":"Lawrence","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.molmed.2013.08.001","article-title":"Nuclear factor kappa B (NF-kappaB) in multiple sclerosis pathology","volume":"19","author":"Prinz","year":"2013","journal-title":"Trends Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1242\/jcs.162404","article-title":"NF-kappaB controls axonal regeneration and degeneration through cell-specific balance of RelA and p50 in the adult CNS","volume":"127","author":"Haenold","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12985-017-0707-7","article-title":"The DNA damage response promotes polyomavirus JC infection by nucleus to cytoplasm NF- kappaB activation","volume":"14","author":"White","year":"2017","journal-title":"Virol. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8696","DOI":"10.1038\/s41598-017-08623-5","article-title":"DNA methylation in demyelinated multiple sclerosis hippocampus","volume":"7","author":"Chomyk","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nn.3588","article-title":"Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains","volume":"17","author":"Huynh","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/mrd.22489","article-title":"The ImageJ ecosystem: An open platform for biomedical image analysis","volume":"82","author":"Schindelin","year":"2015","journal-title":"Mol. Reprod. Dev."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Voigt, D., Scheidt, U., Derfuss, T., Bruck, W., and Junker, A. (2017). Expression of the Antioxidative Enzyme Peroxiredoxin 2 in Multiple Sclerosis Lesions in Relation to Inflammation. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040760"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3342","DOI":"10.1093\/brain\/awp300","article-title":"MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47","volume":"132","author":"Junker","year":"2009","journal-title":"Brain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"250","DOI":"10.5414\/NP300904","article-title":"Clinical Neuropathology practice guide 5-2015: MGMT methylation pyrosequencing in glioblastoma: Unresolved issues and open questions","volume":"34","author":"Bienkowski","year":"2015","journal-title":"Clin. Neuropathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3845\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:58:51Z","timestamp":1760363931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3845"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,8]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22083845"],"URL":"https:\/\/doi.org\/10.3390\/ijms22083845","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,8]]}}}