Promoter hypermethylation of p16 and APC in gastrointestinal cancer patients

Erdem, Beril; Küçükyıldırım, Sibel; Saglar, Emel; Polat, Zülfıkar; Mergen, Hatıce

doi:10.5152/tjg.2014.4791

Cited by 8 publications

(2 citation statements)

References 38 publications

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“…Likewise, CDKN2A is inactivated in more than 80% of BE and EAC tissues ( 34–36 ). Similar molecular abnormalities also occur in gastric cardia neoplasia ( 37–42 ), supporting the contribution of TP53 and CDKN2A to diverse types of adenocarcinogenesis involving the GEJ region. In agreement with these static observations, our dynamic model establishes that TP53/CDKN2A inactivation directly causes biologic and molecular features consistent with GEJ neoplastic progression.…”

Section: Discussionmentioning

confidence: 58%

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Zhao

Cheng

Kalra

et al. 2022

Preprint

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Inactivation of the tumor suppressor genes TP53 and CDKN2A occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, due to a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have been incompletely characterized. Here we report the development of the first wild-type primary human GEJ organoid model, as well as a CRISPR-edited transformed GEJ organoid model. CRISPR/Cas9 engineering to inactivate TP53 and CDKN2A (TP53/CDKN2AKO) in GEJ organoids induced morphologic dysplasia as well as pro-neoplastic features in vitro and tumor formation in vivo. Notably, lipidomic profiling identified several Platelet-Activating Factors (PTAFs) among the most upregulated lipids in CRISPR-edited organoids; and importantly, PTAF/PTAFR abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) significantly blocked proliferation and other pro-neoplastic features of TP53/CDKN2AKO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts derived from Eso26, an established esophageal adenocarcinoma (EAC) cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly Forkhead Box M1 (FOXM1). Importantly, FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. In summary, we established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and discovered a potential cancer-therapeutic strategy, while providing insights into pro-neoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia.One Sentence SummaryNovel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model.Graphic Abstract

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Section: Discussionmentioning

confidence: 58%

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Zhao

Cheng

Kalra

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Likewise, CDKN2A is inactivated in more than 80% of BE and EAC tissues (34)(35)(36). Similar molecular abnormalities also occur in gastric cardia neoplasia (37)(38)(39)(40)(41)(42), supporting the contribution of TP53 and CDKN2A to diverse types of adenocarcinogenesis involving the GEJ region. In agreement with these static observations, our dynamic model establishes that TP53/CDKN2A inactivation directly causes biologic and molecular features consistent with GEJ neoplastic progression.…”

Section: Discussionmentioning

confidence: 72%

Generation and multiomic profiling of aTP53/CDKN2Adouble-knockout gastroesophageal junction organoid model

et al. 2022

View full text Add to dashboard Cite

Inactivation of the tumor suppressor genes tumor protein p53 ( TP53 ) and cyclin-dependent kinase inhibitor 2A ( CDKN2A ) occurs early during gastroesophageal junction (GEJ) tumorigenesis. However, because of a paucity of GEJ-specific disease models, cancer-promoting consequences of TP53 and CDKN2A inactivation at the GEJ have not been characterized. Here, we report the development of a wild-type primary human GEJ organoid model and a CRISPR-edited transformed GEJ organoid model. CRISPR-Cas9–mediated TP53 and CDKN2A knockout ( TP53/CDKN2A KO ) in GEJ organoids induced morphologic dysplasia and proneoplastic features in vitro and tumor formation in vivo. Lipidomic profiling identified several platelet-activating factors (PTAFs) among the most up-regulated lipids in CRISPR-edited organoids. PTAF/PTAF receptor (PTAFR) abrogation by siRNA knockdown or a pharmacologic inhibitor (WEB2086) reduced proliferation and other proneoplastic features of TP53/CDKN2A KO GEJ organoids in vitro and tumor formation in vivo. In addition, murine xenografts of Eso26, an established human esophageal adenocarcinoma cell line, were suppressed by WEB2086. Mechanistically, TP53/CDKN2A dual inactivation disrupted both the transcriptome and the DNA methylome, likely mediated by key transcription factors, particularly forkhead box M1 (FOXM1). FOXM1 activated PTAFR transcription by binding to the PTAFR promoter, further amplifying the PTAF-PTAFR pathway. Together, these studies established a robust model system for investigating early GEJ neoplastic events, identified crucial metabolic and epigenomic changes occurring during GEJ model tumorigenesis, and revealed a potential cancer therapeutic strategy. This work provides insights into proneoplastic mechanisms associated with TP53/CDKN2A inactivation in early GEJ neoplasia, which may facilitate early diagnosis and prevention of GEJ neoplasms.

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Composition of the colon microbiota in the individuals with inflammatory bowel disease and colon cancer

et al. 2023

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Promoter hypermethylation of p16 and APC in gastrointestinal cancer patients

Cited by 8 publications

References 38 publications

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Novel tumorigenic FOXM1-PTAFR-PTAF axis revealed by multi-omic profiling in TP53/CDKN2A-double knockout human gastroesophageal junction organoid model

Generation and multiomic profiling of aTP53/CDKN2Adouble-knockout gastroesophageal junction organoid model

Composition of the colon microbiota in the individuals with inflammatory bowel disease and colon cancer

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