<scp>DNA</scp> ‐hypermethylated human gastric cancer circumvents apoptosis in the absence of <scp> <i>TP53</i> </scp> mutation

p53 is one of the most important tumour suppressors exerting antitumour effects primarily via apoptosis. TP53 mutations are common in gastric tumorigenesis; however, nearly half of the gastric cancers (GCs) remain wildtype TP53 (TP53_WT). We investigated epigenetic/genetic profiles of GCs and the carcinogenic mechanisms underlying GCs with TP53_WT. Comprehensive DNA methylation analysis revealed four DNA methylation epigenotypes (MEs) in GCs, namely, high ME (HME), extremely HME (E-HME), low ME (LME), and extremely LME (E-LME). E-HME matched Epstein-Barr virus (EBV)-positive GC (E-HME/EBV). HME can be further categorised into MLH1-deficient (HME_MLH1(-)) and -proficient cases. The Cancer Genome Atlas data confirmed that HME_MLH1(-)/microsatellite instability (MSI) and E-HME/EBV cases significantly retained TP53_WT and had higher MDM2 expression levels than other MEs. We hypothesised that apoptosis pathways in TP53_WT GC may be suppressed post-transcriptionally by activated MDM2. Short hairpin RNA-mediated MDM2 knockdown and the p53-MDM2 inhibitors, nutlin-3 and RG7388, induced apoptosis in TP53_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-hypermethylated GC cases, HME_MLH1(-)/MSI and E-HME/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of TP53 mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway. © 2025 The Pathological Society of Great Britain and Ireland.