{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:44:32Z","timestamp":1792115072253,"version":"4.4.0"},"reference-count":96,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K16347"],"award-info":[{"award-number":["JP20K16347"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20gm1310006"],"award-info":[{"award-number":["JP20gm1310006"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Discov Onc"],"DOI":"10.1007\/s12672-025-02971-9","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T21:48:45Z","timestamp":1750283325000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["How chronic inflammation fuels carcinogenesis as an environmental epimutagen"],"prefix":"10.1007","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4814-8616","authenticated-orcid":false,"given":"Yu-Yu","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui","family":"Ohashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3405-7817","authenticated-orcid":false,"given":"Toshikazu","family":"Ushijima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,18]]},"reference":[{"key":"2971_CR1","doi-asserted-by":"crossref","unstructured":"Waldum H, Fossmark R. Inflammation and digestive Cancer. Int J Mol Sci. 2023;24(17):13503.","DOI":"10.3390\/ijms241713503"},{"key":"2971_CR2","doi-asserted-by":"publisher","first-page":"768098","DOI":"10.3389\/fimmu.2021.768098","volume":"12","author":"W Liu","year":"2021","unstructured":"Liu W, et al. Cancer Evo-Dev: a theory of inflammation-induced oncogenesis. Front Immunol. 2021;12:768098.","journal-title":"Front Immunol"},{"issue":"11","key":"2971_CR3","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1016\/j.freeradbiomed.2010.09.006","volume":"49","author":"S Reuter","year":"2010","unstructured":"Reuter S, et al. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603\u201316.","journal-title":"Free Radic Biol Med"},{"issue":"1","key":"2971_CR4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s00018-015-2045-5","volume":"73","author":"M Rokavec","year":"2016","unstructured":"Rokavec M, Oner MG, Hermeking H. lnflammation-induced epigenetic switches in cancer. Cell Mol Life Sci. 2016;73(1):23\u201339.","journal-title":"Cell Mol Life Sci"},{"key":"2971_CR5","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/bs.pmbts.2016.09.002","volume":"144","author":"AR Maiuri","year":"2016","unstructured":"Maiuri AR, O\u2019Hagan HM. Interplay between inflammation and epigenetic changes in cancer. Prog Mol Biol Transl Sci. 2016;144:69\u2013117.","journal-title":"Prog Mol Biol Transl Sci"},{"issue":"23","key":"2971_CR6","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.3748\/wjg.v25.i23.2863","volume":"25","author":"ZH Yang","year":"2019","unstructured":"Yang ZH, Dang YQ, Ji G. Role of epigenetics in transformation of inflammation into colorectal cancer. World J Gastroenterol. 2019;25(23):2863\u201377.","journal-title":"World J Gastroenterol"},{"issue":"8","key":"2971_CR7","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/nrgastro.2017.53","volume":"14","author":"N Padmanabhan","year":"2017","unstructured":"Padmanabhan N, Ushijima T, Tan P. How to stomach an epigenetic insult: the gastric cancer epigenome. Nat Rev Gastroenterol Hepatol. 2017;14(8):467\u201378.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"10","key":"2971_CR8","doi-asserted-by":"publisher","first-page":"5370","DOI":"10.1172\/JCI124070","volume":"130","author":"H Takeshima","year":"2020","unstructured":"Takeshima H, et al. TET repression and increased DNMT activity synergistically induce aberrant DNA methylation. J Clin Invest. 2020;130(10):5370\u20139.","journal-title":"J Clin Invest"},{"issue":"10","key":"2971_CR9","doi-asserted-by":"publisher","first-page":"2120","DOI":"10.1158\/0008-5472.CAN-14-3295","volume":"75","author":"M Abu-Remaileh","year":"2015","unstructured":"Abu-Remaileh M, et al. Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer. Cancer Res. 2015;75(10):2120\u201330.","journal-title":"Cancer Res"},{"issue":"4","key":"2971_CR10","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1158\/0008-5472.CAN-09-2755","volume":"70","author":"T Niwa","year":"2010","unstructured":"Niwa T, et al. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 2010;70(4):1430\u201340.","journal-title":"Cancer Res"},{"key":"2971_CR11","doi-asserted-by":"publisher","first-page":"1513654","DOI":"10.3389\/fonc.2024.1513654","volume":"14","author":"ZA Sherif","year":"2024","unstructured":"Sherif ZA, Ogunwobi OO, Ressom HW. Mechanisms and technologies in cancer epigenetics. Front Oncol. 2024;14:1513654.","journal-title":"Front Oncol"},{"issue":"12","key":"2971_CR12","doi-asserted-by":"publisher","first-page":"3938","DOI":"10.1158\/1078-0432.CCR-08-2783","volume":"15","author":"JP Issa","year":"2009","unstructured":"Issa JP, Kantarjian HM. Targeting DNA methylation. Clin Cancer Res. 2009;15(12):3938\u201346.","journal-title":"Clin Cancer Res"},{"issue":"1","key":"2971_CR13","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/0092-8674(80)90237-8","volume":"20","author":"PA Jones","year":"1980","unstructured":"Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20(1):85\u201393.","journal-title":"Cell"},{"issue":"5618","key":"2971_CR14","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1126\/science.1083558","volume":"300","author":"F Gaudet","year":"2003","unstructured":"Gaudet F, et al. Induction of tumors in mice by genomic hypomethylation. Science. 2003;300(5618):489\u201392.","journal-title":"Science"},{"issue":"6697","key":"2971_CR15","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/25779","volume":"395","author":"RZ Chen","year":"1998","unstructured":"Chen RZ, et al. DNA hypomethylation leads to elevated mutation rates. Nature. 1998;395(6697):89\u201393.","journal-title":"Nature"},{"issue":"2","key":"2971_CR16","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1093\/carcin\/20.2.343","volume":"20","author":"LE Lantry","year":"1999","unstructured":"Lantry LE, et al. 5-Aza-2\u2019-deoxycytidine is chemopreventive in a 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone-induced primary mouse lung tumor model. Carcinogenesis. 1999;20(2):343\u20136.","journal-title":"Carcinogenesis"},{"issue":"7","key":"2971_CR17","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1038\/bjp.2008.17","volume":"153","author":"H Hagiwara","year":"2008","unstructured":"Hagiwara H, et al. 5-Aza-2\u2019-deoxycytidine suppresses human renal carcinoma cell growth in a xenograft model via up-regulation of the connexin 32 gene. Br J Pharmacol. 2008;153(7):1373\u201381.","journal-title":"Br J Pharmacol"},{"issue":"1","key":"2971_CR18","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s11095-024-03810-2","volume":"42","author":"HH Hsieh","year":"2025","unstructured":"Hsieh HH, et al. Epigenetic modifications as novel therapeutic strategies of Cancer chemoprevention by phytochemicals. Pharm Res. 2025;42(1):69\u201378.","journal-title":"Pharm Res"},{"issue":"1","key":"2971_CR19","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1158\/0008-5472.CAN-05-2020","volume":"66","author":"MT McCabe","year":"2006","unstructured":"McCabe MT, et al. Inhibition of DNA methyltransferase activity prevents tumorigenesis in a mouse model of prostate cancer. Cancer Res. 2006;66(1):385\u201392.","journal-title":"Cancer Res"},{"issue":"12","key":"2971_CR20","doi-asserted-by":"publisher","first-page":"2434","DOI":"10.1093\/carcin\/bgm206","volume":"28","author":"Y Kanai","year":"2007","unstructured":"Kanai Y, Hirohashi S. Alterations of DNA methylation associated with abnormalities of DNA methyltransferases in human cancers during transition from a precancerous to a malignant state. Carcinogenesis. 2007;28(12):2434\u201342.","journal-title":"Carcinogenesis"},{"issue":"10","key":"2971_CR21","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1093\/carcin\/bgn170","volume":"29","author":"W Gao","year":"2008","unstructured":"Gao W, et al. Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas. Carcinogenesis. 2008;29(10):1901\u201310.","journal-title":"Carcinogenesis"},{"issue":"2","key":"2971_CR22","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1136\/gutjnl-2023-329492","volume":"73","author":"C Takeuchi","year":"2024","unstructured":"Takeuchi C, et al. Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation. Gut. 2024;73(2):255\u201367.","journal-title":"Gut"},{"issue":"1","key":"2971_CR23","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1038\/s41420-024-01803-z","volume":"10","author":"X Yu","year":"2024","unstructured":"Yu X, et al. Cancer epigenetics: from laboratory studies and clinical trials to precision medicine. Cell Death Discov. 2024;10(1):28.","journal-title":"Cell Death Discov"},{"key":"2971_CR24","doi-asserted-by":"crossref","unstructured":"Perner F, et al. Therapeutic targeting of chromatin alterations in leukemia and solid tumors. Int J Cancer. 2025;1\u201327.","DOI":"10.1002\/ijc.35389"},{"key":"2971_CR25","doi-asserted-by":"publisher","first-page":"175883592312205","DOI":"10.1177\/17588359231220511","volume":"16","author":"F Geissler","year":"2024","unstructured":"Geissler F, et al. The role of aberrant DNA methylation in cancer initiation and clinical impacts. Ther Adv Med Oncol. 2024;16:17588359231220511.","journal-title":"Ther Adv Med Oncol"},{"issue":"1","key":"2971_CR26","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s11523-017-0546-x","volume":"13","author":"M Chovanec","year":"2018","unstructured":"Chovanec M, et al. Incorporating DNA methyltransferase inhibitors (DNMTis) in the treatment of genitourinary malignancies: A systematic review. Target Oncol. 2018;13(1):49\u201360.","journal-title":"Target Oncol"},{"issue":"20","key":"2971_CR27","doi-asserted-by":"publisher","first-page":"6254","DOI":"10.1158\/1078-0432.CCR-17-0235","volume":"23","author":"N Shen","year":"2017","unstructured":"Shen N, et al. Inactivation of receptor tyrosine kinases reverts aberrant DNA methylation in acute myeloid leukemia. Clin Cancer Res. 2017;23(20):6254\u201366.","journal-title":"Clin Cancer Res"},{"issue":"3","key":"2971_CR28","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1038\/mt.2015.226","volume":"24","author":"C Huisman","year":"2016","unstructured":"Huisman C, et al. Re-expression of selected epigenetically silenced candidate tumor suppressor genes in cervical Cancer by TET2-directed demethylation. Mol Ther. 2016;24(3):536\u201347.","journal-title":"Mol Ther"},{"issue":"4","key":"2971_CR29","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1007\/s00280-008-0773-z","volume":"63","author":"Y Song","year":"2009","unstructured":"Song Y, Zhang C. Hydralazine inhibits human cervical cancer cell growth in vitro in association with APC demethylation and re-expression. Cancer Chemother Pharmacol. 2009;63(4):605\u201313.","journal-title":"Cancer Chemother Pharmacol"},{"issue":"2","key":"2971_CR30","first-page":"142","volume":"40","author":"T Ushijima","year":"2007","unstructured":"Ushijima T. Epigenetic field for cancerization. J Biochem Mol Biol. 2007;40(2):142\u201350.","journal-title":"J Biochem Mol Biol"},{"issue":"1","key":"2971_CR31","doi-asserted-by":"publisher","first-page":"6874","DOI":"10.1038\/s41598-023-33932-3","volume":"13","author":"N Besselink","year":"2023","unstructured":"Besselink N, et al. The genome-wide mutational consequences of DNA hypomethylation. Sci Rep. 2023;13(1):6874.","journal-title":"Sci Rep"},{"issue":"2","key":"2971_CR32","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.ccell.2019.01.015","volume":"35","author":"T Ushijima","year":"2019","unstructured":"Ushijima T, Suzuki H. The origin of CIMP, at last. Cancer Cell. 2019;35(2):165\u20137.","journal-title":"Cancer Cell"},{"issue":"6127","key":"2971_CR33","first-page":"1546","volume":"339","author":"B Vogelstein","year":"2013","unstructured":"Vogelstein B, et al. Cancer Genome Landscapes Sci. 2013;339(6127):1546\u201358.","journal-title":"Cancer Genome Landscapes Sci"},{"issue":"7793","key":"2971_CR34","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s41586-020-1969-6","volume":"578","author":"IT Consortium","year":"2020","unstructured":"Consortium IT. Pan-cancer analysis of whole genomes. Nature. 2020;578(7793):82\u201393.","journal-title":"Nature"},{"issue":"1","key":"2971_CR35","doi-asserted-by":"publisher","first-page":"12742","DOI":"10.1038\/s41598-023-39608-2","volume":"13","author":"M Sinkala","year":"2023","unstructured":"Sinkala M. Mutational landscape of cancer-driver genes across human cancers. Sci Rep. 2023;13(1):12742.","journal-title":"Sci Rep"},{"issue":"4","key":"2971_CR36","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1016\/j.ccell.2018.03.010","volume":"33","author":"Y Liu","year":"2018","unstructured":"Liu Y, et al. Comparative molecular analysis of Gastrointestinal adenocarcinomas. Cancer Cell. 2018;33(4):721\u2013e7358.","journal-title":"Cancer Cell"},{"issue":"4","key":"2971_CR37","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/s41568-021-00335-3","volume":"21","author":"N Kakiuchi","year":"2021","unstructured":"Kakiuchi N, Ogawa S. Clonal expansion in non-cancer tissues. Nat Rev Cancer. 2021;21(4):239\u201356.","journal-title":"Nat Rev Cancer"},{"issue":"3","key":"2971_CR38","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1002\/cncr.11090","volume":"97","author":"G Garcia-Manero","year":"2003","unstructured":"Garcia-Manero G, et al. Aberrant DNA methylation in pediatric patients with acute lymphocytic leukemia. Cancer. 2003;97(3):695\u2013702.","journal-title":"Cancer"},{"issue":"3 Pt 1","key":"2971_CR39","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1158\/1078-0432.CCR-05-2096","volume":"12","author":"T Maekita","year":"2006","unstructured":"Maekita T, et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res. 2006;12(3 Pt 1):989\u201395.","journal-title":"Clin Cancer Res"},{"key":"2971_CR40","doi-asserted-by":"publisher","first-page":"1148722","DOI":"10.3389\/fimmu.2023.1148722","volume":"14","author":"N Zhang","year":"2023","unstructured":"Zhang N, et al. Insights into the role of nucleotide methylation in metabolic-associated fatty liver disease. Front Immunol. 2023;14:1148722.","journal-title":"Front Immunol"},{"issue":"5","key":"2971_CR41","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1007\/s10120-023-01399-w","volume":"26","author":"T Irie","year":"2023","unstructured":"Irie T, et al. The methylation level of a single cancer risk marker gene reflects methylation burden in gastric mucosa. Gastric Cancer. 2023;26(5):667\u201376.","journal-title":"Gastric Cancer"},{"issue":"8","key":"2971_CR42","doi-asserted-by":"publisher","first-page":"2251","DOI":"10.1038\/s41591-024-03014-6","volume":"30","author":"L Schreiberhuber","year":"2024","unstructured":"Schreiberhuber L, et al. Cervical cancer screening using DNA methylation triage in a real-world population. Nat Med. 2024;30(8):2251\u20137.","journal-title":"Nat Med"},{"issue":"6","key":"2971_CR43","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1073\/pnas.1717340115","volume":"115","author":"S Yamashita","year":"2018","unstructured":"Yamashita S, et al. Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues. Proc Natl Acad Sci U S A. 2018;115(6):1328\u201333.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2971_CR44","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1093\/carcin\/bgq219","volume":"32","author":"K Hur","year":"2011","unstructured":"Hur K, et al. Insufficient role of cell proliferation in aberrant DNA methylation induction and involvement of specific types of inflammation. Carcinogenesis. 2011;32(1):35\u201341.","journal-title":"Carcinogenesis"},{"issue":"3","key":"2971_CR45","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/BF02592984","volume":"26","author":"D Basso","year":"1996","unstructured":"Basso D, et al. Helicobacter pylori infection enhances mucosal interleukin-1 beta, interleukin-6, and the soluble receptor of interleukin-2. Int J Clin Lab Res. 1996;26(3):207\u201310.","journal-title":"Int J Clin Lab Res"},{"issue":"2","key":"2971_CR46","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1136\/jcp.48.2.133","volume":"48","author":"XG Fan","year":"1995","unstructured":"Fan XG, et al. Increased gastric production of interleukin-8 and tumour necrosis factor in patients with Helicobacter pylori infection. J Clin Pathol. 1995;48(2):133\u20136.","journal-title":"J Clin Pathol"},{"issue":"4","key":"2971_CR47","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1136\/gut.41.4.442","volume":"41","author":"Y Yamaoka","year":"1997","unstructured":"Yamaoka Y, et al. Induction of various cytokines and development of severe mucosal inflammation by CagA gene positive Helicobacter pylori strains. Gut. 1997;41(4):442\u201351.","journal-title":"Gut"},{"issue":"4","key":"2971_CR48","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/sj.bjc.6605530","volume":"102","author":"Y Wu","year":"2010","unstructured":"Wu Y, Zhou BP. TNF-alpha\/NF-kappaB\/Snail pathway in cancer cell migration and invasion. Br J Cancer. 2010;102(4):639\u201344.","journal-title":"Br J Cancer"},{"key":"2971_CR49","doi-asserted-by":"publisher","first-page":"102673","DOI":"10.1016\/j.dnarep.2019.102673","volume":"83","author":"J Kay","year":"2019","unstructured":"Kay J, et al. Inflammation-induced DNA damage, mutations and cancer. DNA Repair (Amst). 2019;83:102673.","journal-title":"DNA Repair (Amst)"},{"issue":"3","key":"2971_CR50","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/j.bbrc.2009.08.003","volume":"388","author":"Y Katayama","year":"2009","unstructured":"Katayama Y, Takahashi M, Kuwayama H. Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochem Biophys Res Commun. 2009;388(3):496\u2013500.","journal-title":"Biochem Biophys Res Commun"},{"issue":"11","key":"2971_CR51","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.1084\/jem.190.11.1595","volume":"190","author":"A Hmadcha","year":"1999","unstructured":"Hmadcha A, et al. Methylation-dependent gene Silencing induced by Interleukin 1beta via nitric oxide production. J Exp Med. 1999;190(11):1595\u2013604.","journal-title":"J Exp Med"},{"key":"2971_CR52","doi-asserted-by":"crossref","unstructured":"Thomas D, et al. Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome. Res Sq. 2024.","DOI":"10.21203\/rs.3.rs-4131804\/v1"},{"issue":"9","key":"2971_CR53","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1248\/bpb.b15-00364","volume":"38","author":"K Okuda","year":"2015","unstructured":"Okuda K, Ito A, Uehara T. Regulation of histone deacetylase 6 activity via S-Nitrosylation. Biol Pharm Bull. 2015;38(9):1434\u20137.","journal-title":"Biol Pharm Bull"},{"issue":"49","key":"2971_CR54","doi-asserted-by":"publisher","first-page":"19183","DOI":"10.1073\/pnas.0805514105","volume":"105","author":"C Colussi","year":"2008","unstructured":"Colussi C, et al. HDAC2 Blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment. Proc Natl Acad Sci U S A. 2008;105(49):19183\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"22","key":"2971_CR55","doi-asserted-by":"publisher","first-page":"16004","DOI":"10.1074\/jbc.M112.432294","volume":"288","author":"JR Hickok","year":"2013","unstructured":"Hickok JR, et al. Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem. 2013;288(22):16004\u201315.","journal-title":"J Biol Chem"},{"issue":"1","key":"2971_CR56","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s00535-009-0142-7","volume":"45","author":"T Nakajima","year":"2010","unstructured":"Nakajima T, et al. Persistence of a component of DNA methylation in gastric mucosae after Helicobacter pylori eradication. J Gastroenterol. 2010;45(1):37\u201344.","journal-title":"J Gastroenterol"},{"issue":"5","key":"2971_CR57","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1007\/s00535-006-1846-6","volume":"41","author":"T Ushijima","year":"2006","unstructured":"Ushijima T, Nakajima T, Maekita T. DNA methylation as a marker for the past and future. J Gastroenterol. 2006;41(5):401\u20137.","journal-title":"J Gastroenterol"},{"issue":"7","key":"2971_CR58","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1111\/j.1572-0241.2007.01284.x","volume":"102","author":"F Perri","year":"2007","unstructured":"Perri F, et al. Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication. Am J Gastroenterol. 2007;102(7):1361\u201371.","journal-title":"Am J Gastroenterol"},{"issue":"1","key":"2971_CR59","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1186\/s13148-019-0789-8","volume":"11","author":"S Yamashita","year":"2019","unstructured":"Yamashita S, et al. Distinct DNA methylation targets by aging and chronic inflammation: a pilot study using gastric mucosa infected with Helicobacter pylori. Clin Epigenetics. 2019;11(1):191.","journal-title":"Clin Epigenetics"},{"issue":"20","key":"2971_CR60","doi-asserted-by":"publisher","first-page":"4969","DOI":"10.1002\/cncr.27519","volume":"118","author":"FY Huang","year":"2012","unstructured":"Huang FY, et al. Helicobacter pylori induces promoter methylation of E-cadherin via interleukin-1beta activation of nitric oxide production in gastric cancer cells. Cancer. 2012;118(20):4969\u201380.","journal-title":"Cancer"},{"issue":"20","key":"2971_CR61","doi-asserted-by":"publisher","first-page":"3043","DOI":"10.3748\/wjg.v19.i20.3043","volume":"19","author":"MC Alvarez","year":"2013","unstructured":"Alvarez MC, et al. MGMT and MLH1 methylation in Helicobacter pylori-infected children and adults. World J Gastroenterol. 2013;19(20):3043\u201351.","journal-title":"World J Gastroenterol"},{"issue":"6562","key":"2971_CR62","doi-asserted-by":"publisher","first-page":"1474","DOI":"10.1126\/science.abh1645","volume":"373","author":"T Ushijima","year":"2021","unstructured":"Ushijima T, Clark SJ, Tan P. Mapping genomic and epigenomic evolution in cancer ecosystems. Science. 2021;373(6562):1474\u20139.","journal-title":"Science"},{"issue":"2","key":"2971_CR63","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1053\/j.gastro.2007.06.026","volume":"133","author":"P Correa","year":"2007","unstructured":"Correa P, Houghton J. Carcinogenesis of Helicobacter pylori. Gastroenterology. 2007;133(2):659\u201372.","journal-title":"Gastroenterology"},{"issue":"3","key":"2971_CR64","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1136\/gutjnl-2014-307094","volume":"64","author":"K Asada","year":"2015","unstructured":"Asada K, et al. Demonstration of the usefulness of epigenetic cancer risk prediction by a multicentre prospective cohort study. Gut. 2015;64(3):388\u201396.","journal-title":"Gut"},{"key":"2971_CR65","doi-asserted-by":"publisher","unstructured":"Yamada H et al. Precision risk stratification of primary gastric cancer after eradication of H. pylori by a DNA methylation marker: a multicentre prospective study. Gut. 2025. https:\/\/doi.org\/10.1136\/gutjnl-2025-335039.","DOI":"10.1136\/gutjnl-2025-335039"},{"issue":"17","key":"2971_CR66","first-page":"3942","volume":"58","author":"CJ Hsieh","year":"1998","unstructured":"Hsieh CJ, et al. Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res. 1998;58(17):3942\u20135.","journal-title":"Cancer Res"},{"issue":"2","key":"2971_CR67","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1002\/gcc.10101","volume":"35","author":"P Azarschab","year":"2002","unstructured":"Azarschab P, et al. Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis. Genes Chromosomes Cancer. 2002;35(2):121\u20136.","journal-title":"Genes Chromosomes Cancer"},{"issue":"1","key":"2971_CR68","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1007\/s12010-019-03017-x","volume":"189","author":"RH Salama","year":"2019","unstructured":"Salama RH, et al. Interrelations of apoptotic and cellular senescence genes methylation in inflammatory bowel disease subtypes and colorectal carcinoma in Egyptians patients. Appl Biochem Biotechnol. 2019;189(1):330\u201343.","journal-title":"Appl Biochem Biotechnol"},{"issue":"11","key":"2971_CR69","doi-asserted-by":"publisher","first-page":"2300","DOI":"10.1002\/(SICI)1097-0142(19961201)78:11<2300::AID-CNCR5>3.0.CO;2-Q","volume":"78","author":"L Gloria","year":"1996","unstructured":"Gloria L, et al. DNA hypomethylation and proliferative activity are increased in the rectal mucosa of patients with long-standing ulcerative colitis. Cancer. 1996;78(11):2300\u20136.","journal-title":"Cancer"},{"issue":"11","key":"2971_CR70","doi-asserted-by":"publisher","first-page":"3045","DOI":"10.4049\/jimmunol.1900467","volume":"203","author":"S Qi","year":"2019","unstructured":"Qi S, et al. Uhrf1-Mediated Tnf-alpha gene methylation controls Proinflammatory macrophages in experimental colitis resembling inflammatory bowel disease. J Immunol. 2019;203(11):3045\u201353.","journal-title":"J Immunol"},{"issue":"5","key":"2971_CR71","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.1172\/JCI69592","volume":"124","author":"F Antignano","year":"2014","unstructured":"Antignano F, et al. Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation. J Clin Invest. 2014;124(5):1945\u201355.","journal-title":"J Clin Invest"},{"key":"2971_CR72","doi-asserted-by":"crossref","unstructured":"Kim TO, et al. Genome-wide analysis of the DNA methylation profile identifies the fragile histidine triad (FHIT) gene as a new promising biomarker of Crohn\u2019s disease. J Clin Med. 2020;9(5):1338.","DOI":"10.3390\/jcm9051338"},{"issue":"10","key":"2971_CR73","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/ibd\/izaa074","volume":"26","author":"S Samarani","year":"2020","unstructured":"Samarani S, et al. CpG methylation in TGFbeta1 and IL-6 genes as surrogate biomarkers for diagnosis of IBD in children. Inflamm Bowel Dis. 2020;26(10):1572\u20138.","journal-title":"Inflamm Bowel Dis"},{"issue":"28","key":"2971_CR74","doi-asserted-by":"publisher","first-page":"e309","DOI":"10.1097\/MD.0000000000000309","volume":"93","author":"PS Karatzas","year":"2014","unstructured":"Karatzas PS, et al. DNA methylation profile of genes involved in inflammation and autoimmunity in inflammatory bowel disease. Med (Baltim). 2014;93(28):e309.","journal-title":"Med (Baltim)"},{"issue":"5","key":"2971_CR75","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1016\/j.cgh.2018.05.004","volume":"17","author":"JB Kisiel","year":"2019","unstructured":"Kisiel JB, et al. Analysis of DNA methylation at specific loci in stool samples detects colorectal Cancer and High-Grade dysplasia in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2019;17(5):914\u201321. e5.","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"12","key":"2971_CR76","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1007\/s00432-015-1972-8","volume":"141","author":"C Gerecke","year":"2015","unstructured":"Gerecke C, et al. Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer. J Cancer Res Clin Oncol. 2015;141(12):2097\u2013107.","journal-title":"J Cancer Res Clin Oncol"},{"issue":"6","key":"2971_CR77","doi-asserted-by":"publisher","first-page":"2467","DOI":"10.3892\/or.2014.3142","volume":"31","author":"H Jimenez-Wences","year":"2014","unstructured":"Jimenez-Wences H, Peralta-Zaragoza O, Fernandez-Tilapa G. Human papilloma virus, DNA methylation and MicroRNA expression in cervical cancer (Review). Oncol Rep. 2014;31(6):2467\u201376.","journal-title":"Oncol Rep"},{"issue":"3","key":"2971_CR78","first-page":"584","volume":"7","author":"AK Virmani","year":"2001","unstructured":"Virmani AK, et al. Aberrant methylation during cervical carcinogenesis. Clin Cancer Res. 2001;7(3):584\u20139.","journal-title":"Clin Cancer Res"},{"issue":"10","key":"2971_CR79","doi-asserted-by":"publisher","first-page":"3396","DOI":"10.1158\/1078-0432.CCR-03-0143","volume":"10","author":"A Widschwendter","year":"2004","unstructured":"Widschwendter A, et al. Analysis of aberrant DNA methylation and human papillomavirus DNA in cervicovaginal specimens to detect invasive cervical cancer and its precursors. Clin Cancer Res. 2004;10(10):3396\u2013400.","journal-title":"Clin Cancer Res"},{"key":"2971_CR80","doi-asserted-by":"publisher","first-page":"p5240127","DOI":"10.1155\/2016\/5240127","volume":"2016","author":"A Cianciulli","year":"2016","unstructured":"Cianciulli A, et al. Folic acid is able to polarize the inflammatory response in LPS activated microglia by regulating multiple signaling pathways. Mediators Inflamm. 2016;2016:p5240127.","journal-title":"Mediators Inflamm"},{"issue":"12","key":"2971_CR81","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1182\/blood.2019004158","volume":"136","author":"X Yue","year":"2020","unstructured":"Yue X, Rao A. TET family dioxygenases and the TET activator vitamin C in immune responses and cancer. Blood. 2020;136(12):1394\u2013401.","journal-title":"Blood"},{"issue":"1","key":"2971_CR82","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13148-022-01404-6","volume":"15","author":"A Taira","year":"2023","unstructured":"Taira A, et al. Vitamin C boosts DNA demethylation in TET2 germline mutation carriers. Clin Epigenetics. 2023;15(1):7.","journal-title":"Clin Epigenetics"},{"issue":"20","key":"2971_CR83","doi-asserted-by":"publisher","first-page":"10907","DOI":"10.1073\/pnas.94.20.10907","volume":"94","author":"CQ Zhao","year":"1997","unstructured":"Zhao CQ, et al. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci U S A. 1997;94(20):10907\u201312.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"2971_CR84","doi-asserted-by":"publisher","first-page":"e54147","DOI":"10.15252\/embr.202154147","volume":"23","author":"N Yan","year":"2022","unstructured":"Yan N, et al. Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation. EMBO Rep. 2022;23(6):e54147.","journal-title":"EMBO Rep"},{"issue":"1","key":"2971_CR85","doi-asserted-by":"publisher","first-page":"87","DOI":"10.2217\/epi.09.45","volume":"2","author":"JF Reichard","year":"2010","unstructured":"Reichard JF, Puga A. Effects of arsenic exposure on DNA methylation and epigenetic gene regulation. Epigenomics. 2010;2(1):87\u2013104.","journal-title":"Epigenomics"},{"issue":"2","key":"2971_CR86","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1172\/JCI40706","volume":"120","author":"RK Lin","year":"2010","unstructured":"Lin RK, et al. The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients. J Clin Invest. 2010;120(2):521\u201332.","journal-title":"J Clin Invest"},{"issue":"21","key":"2971_CR87","doi-asserted-by":"publisher","first-page":"9005","DOI":"10.1158\/0008-5472.CAN-08-1276","volume":"68","author":"LA Damiani","year":"2008","unstructured":"Damiani LA, et al. Carcinogen-induced gene promoter hypermethylation is mediated by DNMT1 and causal for transformation of immortalized bronchial epithelial cells. Cancer Res. 2008;68(21):9005\u201314.","journal-title":"Cancer Res"},{"key":"2971_CR88","doi-asserted-by":"crossref","unstructured":"Pepke ML, Hansen SB, Limborg MT. Unraveling host regulation of gut microbiota through the epigenome\u2013microbiome axis. Trends Microbiol. 2024;32(12):1229\u201340.","DOI":"10.1016\/j.tim.2024.05.006"},{"issue":"5","key":"2971_CR89","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.cmet.2011.02.018","volume":"13","author":"DR Donohoe","year":"2011","unstructured":"Donohoe DR, et al. The Microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 2011;13(5):517\u201326.","journal-title":"Cell Metab"},{"issue":"1","key":"2971_CR90","doi-asserted-by":"publisher","first-page":"2022407","DOI":"10.1080\/19490976.2021.2022407","volume":"14","author":"V Woo","year":"2022","unstructured":"Woo V, Alenghat T. Epigenetic regulation by gut microbiota. Gut Microbes. 2022;14(1):2022407.","journal-title":"Gut Microbes"},{"issue":"7","key":"2971_CR91","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1002\/eji.201747122","volume":"48","author":"M Kim","year":"2018","unstructured":"Kim M, et al. Microbial metabolites, short-chain fatty acids, restrain tissue bacterial load, chronic inflammation, and associated cancer in the colon of mice. Eur J Immunol. 2018;48(7):1235\u201347.","journal-title":"Eur J Immunol"},{"issue":"5","key":"2971_CR92","doi-asserted-by":"publisher","first-page":"e0055821","DOI":"10.1128\/msystems.00558-21","volume":"6","author":"M Leclerc","year":"2021","unstructured":"Leclerc M, et al. Nitric oxide impacts human gut microbiota diversity and functionalities. mSystems. 2021;6(5):e0055821.","journal-title":"mSystems"},{"key":"2971_CR93","doi-asserted-by":"publisher","first-page":"112960","DOI":"10.1016\/j.ejca.2023.112960","volume":"191","author":"S Fu","year":"2023","unstructured":"Fu S, Debes JD, Boonstra A. DNA methylation markers in the detection of hepatocellular carcinoma. Eur J Cancer. 2023;191:112960.","journal-title":"Eur J Cancer"},{"issue":"12","key":"2971_CR94","doi-asserted-by":"publisher","first-page":"2068","DOI":"10.1002\/ijc.34186","volume":"151","author":"N Fatemi","year":"2022","unstructured":"Fatemi N, et al. DNA methylation biomarkers in colorectal cancer: clinical applications for precision medicine. Int J Cancer. 2022;151(12):2068\u201381.","journal-title":"Int J Cancer"},{"issue":"12","key":"2971_CR95","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1038\/s41416-021-01571-y","volume":"125","author":"N Hattori","year":"2021","unstructured":"Hattori N, et al. Combination of a synthetic retinoid and a DNA demethylating agent induced differentiation of neuroblastoma through retinoic acid signal reprogramming. Br J Cancer. 2021;125(12):1647\u201356.","journal-title":"Br J Cancer"},{"issue":"8","key":"2971_CR96","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1182\/bloodadvances.2022008362","volume":"7","author":"Y Kurahashi","year":"2023","unstructured":"Kurahashi Y, et al. Dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth in ATL. Blood Adv. 2023;7(8):1545\u201359.","journal-title":"Blood Adv"}],"container-title":["Discover Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-025-02971-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12672-025-02971-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12672-025-02971-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T23:03:25Z","timestamp":1750287805000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12672-025-02971-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,18]]},"references-count":96,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2971"],"URL":"https:\/\/doi.org\/10.1007\/s12672-025-02971-9","relation":{},"ISSN":["2730-6011"],"issn-type":[{"value":"2730-6011","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,18]]},"assertion":[{"value":"2 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"We declare a conflict of interest with Sysmex company, which is developing an epigenetic gastric cancer risk diagnosis.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"We declare a conflict of interest with Sysmex company, which is developing an epigenetic gastric cancer risk diagnosis.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1150"}}