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<jats:p>\n                    p53 is one of the most important tumour suppressors exerting antitumour effects primarily via apoptosis.\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations are common in gastric tumorigenesis; however, nearly half of the gastric cancers (GCs) remain wildtype\n                    <jats:italic>TP53<\/jats:italic>\n                    (\n                    <jats:italic>TP53<\/jats:italic>\n                    _WT). We investigated epigenetic\/genetic profiles of GCs and the carcinogenic mechanisms underlying GCs with\n                    <jats:italic>TP53<\/jats:italic>\n                    _WT. Comprehensive DNA methylation analysis revealed four DNA methylation epigenotypes (MEs) in GCs, namely, high ME (HME), extremely HME (E\u2010HME), low ME (LME), and extremely LME (E\u2010LME). E\u2010HME matched Epstein\u2013Barr virus (EBV)\u2010positive GC (E\u2010HME\/EBV). HME can be further categorised into MLH1\u2010deficient (HME_MLH1(\u2212)) and \u2010proficient cases. The Cancer Genome Atlas data confirmed that HME_MLH1(\u2212)\/microsatellite instability (MSI) and E\u2010HME\/EBV cases significantly retained\n                    <jats:italic>TP53<\/jats:italic>\n                    _WT and had higher\n                    <jats:italic>MDM2<\/jats:italic>\n                    expression levels than other MEs. We hypothesised that apoptosis pathways in\n                    <jats:italic>TP53<\/jats:italic>\n                    _WT GC may be suppressed post\u2010transcriptionally by activated MDM2. Short hairpin RNA\u2010mediated\n                    <jats:italic>MDM2<\/jats:italic>\n                    knockdown and the p53\u2010MDM2 inhibitors, nutlin\u20103 and RG7388, induced apoptosis in\n                    <jats:italic>TP53<\/jats:italic>\n                    _WT GC cells, indicating that activated MDM2 suppressed p53 protein levels and thereby attenuated the downstream p53 pathway activation, which was restored upon MDM2 knockdown or inhibitor treatment. Collectively, DNA\u2010hypermethylated GC cases, HME_MLH1(\u2212)\/MSI and E\u2010HME\/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of\n                    <jats:italic>TP53<\/jats:italic>\n                    mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway. \u00a9 2025 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6480","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T12:21:33Z","timestamp":1760012493000},"page":"435-449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>DNA<\/scp>\n                    \u2010hypermethylated human gastric cancer circumvents apoptosis in the absence of\n                    <scp>\n                      <i>TP53<\/i>\n                    <\/scp>\n                    mutation"],"prefix":"10.1002","volume":"267","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-0276","authenticated-orcid":false,"given":"Yasunobu","family":"Mano","sequence":"first","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine, Chiba University  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Matsusaka","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine, Chiba University  Chiba Japan"},{"name":"Department of Diagnostic Pathology Graduate School of Medicine, Chiba University  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4207-1408","authenticated-orcid":false,"given":"Motoaki","family":"Seki","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology Graduate School of Medicine, Chiba University  Chiba 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