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Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions

SIMPLE SUMMARY: Intestinal metaplasia confers an increased risk of progression to gastric cancer. However, some intestinal metaplasia patients do not develop cancer. The development of robust molecular biomarkers to stratify patients with advanced gastric precursor lesions at risk of cancer progress...

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Autores principales: Gómez, Antonio, Pato, Miguel L., Bujanda, Luis, Sala, Núria, Companioni, Osmel, Cosme, Ángel, Tufano, Martina, Hanly, David J., García, Nadia, Sanz-Anquela, José Miguel, Gisbert, Javier P., López, Consuelo, Elizalde, José Ignacio, Cuatrecasas, Miriam, Andreu, Victoria, Paules, María José, Martín-Arranz, María Dolores, Ortega, Luis, Poves, Elvira, Barrio, Jesús, Torres, María Ángeles, Muñoz, Guillermo, Ferrández, Ángel, Ramírez-Lázaro, María José, Lario, Sergio, González, Carlos A, Esteller, Manel, Berdasco, María
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199626/
https://www.ncbi.nlm.nih.gov/pubmed/34199386
http://dx.doi.org/10.3390/cancers13112760
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author Gómez, Antonio
Pato, Miguel L.
Bujanda, Luis
Sala, Núria
Companioni, Osmel
Cosme, Ángel
Tufano, Martina
Hanly, David J.
García, Nadia
Sanz-Anquela, José Miguel
Gisbert, Javier P.
López, Consuelo
Elizalde, José Ignacio
Cuatrecasas, Miriam
Andreu, Victoria
Paules, María José
Martín-Arranz, María Dolores
Ortega, Luis
Poves, Elvira
Barrio, Jesús
Torres, María Ángeles
Muñoz, Guillermo
Ferrández, Ángel
Ramírez-Lázaro, María José
Lario, Sergio
González, Carlos A
Esteller, Manel
Berdasco, María
author_facet Gómez, Antonio
Pato, Miguel L.
Bujanda, Luis
Sala, Núria
Companioni, Osmel
Cosme, Ángel
Tufano, Martina
Hanly, David J.
García, Nadia
Sanz-Anquela, José Miguel
Gisbert, Javier P.
López, Consuelo
Elizalde, José Ignacio
Cuatrecasas, Miriam
Andreu, Victoria
Paules, María José
Martín-Arranz, María Dolores
Ortega, Luis
Poves, Elvira
Barrio, Jesús
Torres, María Ángeles
Muñoz, Guillermo
Ferrández, Ángel
Ramírez-Lázaro, María José
Lario, Sergio
González, Carlos A
Esteller, Manel
Berdasco, María
author_sort Gómez, Antonio
collection PubMed
description SIMPLE SUMMARY: Intestinal metaplasia confers an increased risk of progression to gastric cancer. However, some intestinal metaplasia patients do not develop cancer. The development of robust molecular biomarkers to stratify patients with advanced gastric precursor lesions at risk of cancer progression will contribute to guiding programs for prevention. Starting from a genome-wide methylation study, we have simplified the detection method regarding candidate-methylation tests to improve their applicability in the clinical environment. We identified CpG methylation at the ZNF793 and RPRM promoters as a common event in intestinal metaplasia and intestinal forms of gastric cancer. Furthermore, we also showed that Helicobacter pylori infection influences DNA methylation in early precursor lesions but not in intestinal metaplasia, suggesting that therapeutic strategies to prevent epigenome reprogramming toward a cancer signature need to be adopted early in the precursor cascade. ABSTRACT: To adopt prevention strategies in gastric cancer, it is imperative to develop robust biomarkers with acceptable costs and feasibility in clinical practice to stratified populations according to risk scores. With this aim, we applied an unbiased genome-wide CpG methylation approach to a discovery cohort composed of gastric cancer (n = 24), and non-malignant precursor lesions (n = 64). Then, candidate-methylation approaches were performed in a validation cohort of precursor lesions obtained from an observational longitudinal study (n = 264), with a 12-year follow-up to identify repression or progression cases. H. pylori stratification and histology were considered to determine their influence on the methylation dynamics. As a result, we ascertained that intestinal metaplasia partially recapitulates patterns of aberrant methylation of intestinal type of gastric cancer, independently of the H. pylori status. Two epigenetically regulated genes in cancer, RPRM and ZNF793, consistently showed increased methylation in intestinal metaplasia with respect to earlier precursor lesions. In summary, our result supports the need to investigate the practical utilities of the quantification of DNA methylation in candidate genes as a marker for disease progression. In addition, the H. pylori-dependent methylation in intestinal metaplasia suggests that pharmacological treatments aimed at H. pylori eradication in the late stages of precursor lesions do not prevent epigenome reprogramming toward a cancer signature.
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spelling pubmed-81996262021-06-14 Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions Gómez, Antonio Pato, Miguel L. Bujanda, Luis Sala, Núria Companioni, Osmel Cosme, Ángel Tufano, Martina Hanly, David J. García, Nadia Sanz-Anquela, José Miguel Gisbert, Javier P. López, Consuelo Elizalde, José Ignacio Cuatrecasas, Miriam Andreu, Victoria Paules, María José Martín-Arranz, María Dolores Ortega, Luis Poves, Elvira Barrio, Jesús Torres, María Ángeles Muñoz, Guillermo Ferrández, Ángel Ramírez-Lázaro, María José Lario, Sergio González, Carlos A Esteller, Manel Berdasco, María Cancers (Basel) Article SIMPLE SUMMARY: Intestinal metaplasia confers an increased risk of progression to gastric cancer. However, some intestinal metaplasia patients do not develop cancer. The development of robust molecular biomarkers to stratify patients with advanced gastric precursor lesions at risk of cancer progression will contribute to guiding programs for prevention. Starting from a genome-wide methylation study, we have simplified the detection method regarding candidate-methylation tests to improve their applicability in the clinical environment. We identified CpG methylation at the ZNF793 and RPRM promoters as a common event in intestinal metaplasia and intestinal forms of gastric cancer. Furthermore, we also showed that Helicobacter pylori infection influences DNA methylation in early precursor lesions but not in intestinal metaplasia, suggesting that therapeutic strategies to prevent epigenome reprogramming toward a cancer signature need to be adopted early in the precursor cascade. ABSTRACT: To adopt prevention strategies in gastric cancer, it is imperative to develop robust biomarkers with acceptable costs and feasibility in clinical practice to stratified populations according to risk scores. With this aim, we applied an unbiased genome-wide CpG methylation approach to a discovery cohort composed of gastric cancer (n = 24), and non-malignant precursor lesions (n = 64). Then, candidate-methylation approaches were performed in a validation cohort of precursor lesions obtained from an observational longitudinal study (n = 264), with a 12-year follow-up to identify repression or progression cases. H. pylori stratification and histology were considered to determine their influence on the methylation dynamics. As a result, we ascertained that intestinal metaplasia partially recapitulates patterns of aberrant methylation of intestinal type of gastric cancer, independently of the H. pylori status. Two epigenetically regulated genes in cancer, RPRM and ZNF793, consistently showed increased methylation in intestinal metaplasia with respect to earlier precursor lesions. In summary, our result supports the need to investigate the practical utilities of the quantification of DNA methylation in candidate genes as a marker for disease progression. In addition, the H. pylori-dependent methylation in intestinal metaplasia suggests that pharmacological treatments aimed at H. pylori eradication in the late stages of precursor lesions do not prevent epigenome reprogramming toward a cancer signature. MDPI 2021-06-02 /pmc/articles/PMC8199626/ /pubmed/34199386 http://dx.doi.org/10.3390/cancers13112760 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gómez, Antonio
Pato, Miguel L.
Bujanda, Luis
Sala, Núria
Companioni, Osmel
Cosme, Ángel
Tufano, Martina
Hanly, David J.
García, Nadia
Sanz-Anquela, José Miguel
Gisbert, Javier P.
López, Consuelo
Elizalde, José Ignacio
Cuatrecasas, Miriam
Andreu, Victoria
Paules, María José
Martín-Arranz, María Dolores
Ortega, Luis
Poves, Elvira
Barrio, Jesús
Torres, María Ángeles
Muñoz, Guillermo
Ferrández, Ángel
Ramírez-Lázaro, María José
Lario, Sergio
González, Carlos A
Esteller, Manel
Berdasco, María
Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions
title Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions
title_full Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions
title_fullStr Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions
title_full_unstemmed Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions
title_short Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions
title_sort follow-up study confirms the presence of gastric cancer dna methylation hallmarks in high-risk precursor lesions
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199626/
https://www.ncbi.nlm.nih.gov/pubmed/34199386
http://dx.doi.org/10.3390/cancers13112760
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