DNA ‐hypermethylated human gastric cancer circumvents apoptosis in the absence of TP53 mutation
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Wiley
2025
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| author | Yasunobu Mano Keisuke Matsusaka Motoaki Seki Kazuko Kita Masaki Fukuyo Bahityar Rahmutulla Genki Usui Ryoji Fujiki Masayuki Urabe Hiroyuki Abe Hisahiro Matsubara Tetsuo Ushiku Yasuyuki Seto Masashi Fukayama Atsushi Kaneda |
| author_facet | Yasunobu Mano Keisuke Matsusaka Motoaki Seki Kazuko Kita Masaki Fukuyo Bahityar Rahmutulla Genki Usui Ryoji Fujiki Masayuki Urabe Hiroyuki Abe Hisahiro Matsubara Tetsuo Ushiku Yasuyuki Seto Masashi Fukayama Atsushi Kaneda Yasunobu Mano Keisuke Matsusaka Motoaki Seki Kazuko Kita Masaki Fukuyo Bahityar Rahmutulla Genki Usui Ryoji Fujiki Masayuki Urabe Hiroyuki Abe Hisahiro Matsubara Tetsuo Ushiku Yasuyuki Seto Masashi Fukayama Atsushi Kaneda |
| collection | Wiley Open Access |
| contents | DNA ‐hypermethylated human gastric cancer circumvents apoptosis in the absence of TP53 mutation Yasunobu Mano Keisuke Matsusaka Motoaki Seki Kazuko Kita Masaki Fukuyo Bahityar Rahmutulla Genki Usui Ryoji Fujiki Masayuki Urabe Hiroyuki Abe Hisahiro Matsubara Tetsuo Ushiku Yasuyuki Seto Masashi Fukayama Atsushi Kaneda The Journal of Pathology Abstract 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. 10.1002/path.6480 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/path.6480 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_path_6480 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2025 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | DNA ‐hypermethylated human gastric cancer circumvents apoptosis in the absence of TP53 mutation Yasunobu Mano Keisuke Matsusaka Motoaki Seki Kazuko Kita Masaki Fukuyo Bahityar Rahmutulla Genki Usui Ryoji Fujiki Masayuki Urabe Hiroyuki Abe Hisahiro Matsubara Tetsuo Ushiku Yasuyuki Seto Masashi Fukayama Atsushi Kaneda The Journal of Pathology DNA ‐hypermethylated human gastric cancer circumvents apoptosis in the absence of TP53 mutation Yasunobu Mano Keisuke Matsusaka Motoaki Seki Kazuko Kita Masaki Fukuyo Bahityar Rahmutulla Genki Usui Ryoji Fujiki Masayuki Urabe Hiroyuki Abe Hisahiro Matsubara Tetsuo Ushiku Yasuyuki Seto Masashi Fukayama Atsushi Kaneda The Journal of Pathology Abstract 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. 10.1002/path.6480 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | DNA ‐hypermethylated human gastric cancer circumvents apoptosis in the absence of TP53 mutation |
| topic | The Journal of Pathology |
| url | https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6480 |