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Noncoding Genomics in Gastric Cancer and the Gastric Precancerous Cascade: Pathogenesis and Biomarkers.

Sandoval-Bórquez A, Saavedra K, Carrasco-Avino G, Garcia-Bloj B, Fry J, Wichmann I, Corvalán AH - Dis. Markers (2015)

Bottom Line: The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics.Noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics.Potential biomarkers are appearing from analyses of noncoding genomics.

View Article: PubMed Central - PubMed

Affiliation: Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, 8330034 Santiago, Chile ; Scientific and Technological Bioresource Nucleus (BIOREN) and Graduate Program in Applied Cell and Molecular Biology, Universidad de La Frontera, 4811230 Temuco, Chile ; UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, 8330034 Santiago, Chile.

ABSTRACT
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death, whose patterns vary among geographical regions and ethnicities. It is a multifactorial disease, and its development depends on infection by Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), host genetic factors, and environmental factors. The heterogeneity of the disease has begun to be unraveled by a comprehensive mutational evaluation of primary tumors. The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics. Noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics. These processes and molecules ultimately control gene expression. Potential biomarkers are appearing from analyses of noncoding genomics. This review focuses on noncoding genomics and potential biomarkers in the context of gastric cancer and the gastric precancerous cascade.

No MeSH data available.


Related in: MedlinePlus

Higher levels of methylation are observed in gastric mucosae of H. pylori-positive volunteers than in H. pylori-negative volunteers. Methylation levels were measured in the corpus and antrum of 56 H. pylori-negative volunteers and 98 H. pylori-positive volunteers. All the eight CGIs (core region of p16, noncore regions of p16 and THBD; core regions of LOX, HRASLS, FLNc, and HAND1; and p41ARC exonic CGI) showed significantly elevated methylation levels (5.4- to 303-fold) in the H. pylori-positive volunteers. Methylation levels in the corpus were at the same levels as those in the antrum (taken with permission from [61]).
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fig2: Higher levels of methylation are observed in gastric mucosae of H. pylori-positive volunteers than in H. pylori-negative volunteers. Methylation levels were measured in the corpus and antrum of 56 H. pylori-negative volunteers and 98 H. pylori-positive volunteers. All the eight CGIs (core region of p16, noncore regions of p16 and THBD; core regions of LOX, HRASLS, FLNc, and HAND1; and p41ARC exonic CGI) showed significantly elevated methylation levels (5.4- to 303-fold) in the H. pylori-positive volunteers. Methylation levels in the corpus were at the same levels as those in the antrum (taken with permission from [61]).

Mentions: DNA methylation is an important event in the regulation of gene expression, affecting all of the pathways in the cellular network [55]. DNA methylation is a process in which cytosines acquire a methyl group in 5′-position only if they are followed by a guanine (CpG site) [56]. This modification results in gene silencing. In this scenario, an emerging catalog of gastric cancer genes altered by DNA methylation has been established [10]. However, there are limited reports addressing the role of DNA methylation in the gastric precancerous cascade. Two studies [57, 58] demonstrated that IM showed a higher methylation index than that of AG, but no differences between IM and dysplasia were observed. Specific genes, such as p16, display up to a 4-fold increase in their methylation status in the progression from dysplasia to gastric cancer. A study by Chan et al. [59] demonstrated that DNA methylation of the CDH-1 gene was associated with H. pylori infection (p = 0.002) [59]. This study, alongside another manuscript by Leung et al. [60] evaluated the presence of DNA methylation in the CDH-1 promoter region before and after eradication of H. pylori. Results from both studies suggest that H. pylori eradication therapy may reverse aberrant DNA methylation in patients with AG. A significant reduction in the methylation density of the promoter region of the CDH-1 gene was also observed [60]. Maekita et al. [61] expanded these findings to other genes in a healthy donor population. Methylation levels were 5.4- to 303-fold higher in H. pylori-positive than in H. pylori-negative subjects (p < 0.0001) (Figure 2). Schneider et al. [62] performed a quantitative analysis of the DNA methylation status of the promoter region of Reprimo (RPRM), a putative tumor suppressor gene in gastric cancer [63], which demonstrated an association of the methylation status of the gene with the presence of virulence factors in the infecting H. pylori strains. Taken together, these findings suggest that H. pylori infection potently induces aberrant DNA methylation. Moreover, DNA methylation not only is induced by H. pylori infection, but also can be reversed by eradication therapy. In other words, aberrant DNA methylation may be considered to explain how environmental factors increase the susceptibility for cancer development [64]. An emerging body of evidence suggests that DNA methylation may be used as novel and specific biomarkers in gastric cancer [65, 66] through the measurement of circulating DNA in serum (cell-free DNA (cfDNA)). In this scenario, we have discovered that RPRM displays differences in methylation levels between nontumor adjacent mucosa (NTAM) and cancer tissue samples (Figure 3(a)) [63]. Methylation status of this gene may be assessed in plasma samples (Figure 3(b)) [67, 68], offering the opportunity for noninvasive detection of gastric cancer. Data presented here suggest that DNA methylation is a good example of how noncoding genomics not only participate in the pathogenesis of gastric cancer but also are a promising family of biomarkers for gastric cancer risk prediction and prognostication. Further validation of candidate methylation markers in independent cohorts will be required to translate to clinical applications.


Noncoding Genomics in Gastric Cancer and the Gastric Precancerous Cascade: Pathogenesis and Biomarkers.

Sandoval-Bórquez A, Saavedra K, Carrasco-Avino G, Garcia-Bloj B, Fry J, Wichmann I, Corvalán AH - Dis. Markers (2015)

Higher levels of methylation are observed in gastric mucosae of H. pylori-positive volunteers than in H. pylori-negative volunteers. Methylation levels were measured in the corpus and antrum of 56 H. pylori-negative volunteers and 98 H. pylori-positive volunteers. All the eight CGIs (core region of p16, noncore regions of p16 and THBD; core regions of LOX, HRASLS, FLNc, and HAND1; and p41ARC exonic CGI) showed significantly elevated methylation levels (5.4- to 303-fold) in the H. pylori-positive volunteers. Methylation levels in the corpus were at the same levels as those in the antrum (taken with permission from [61]).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4563069&req=5

fig2: Higher levels of methylation are observed in gastric mucosae of H. pylori-positive volunteers than in H. pylori-negative volunteers. Methylation levels were measured in the corpus and antrum of 56 H. pylori-negative volunteers and 98 H. pylori-positive volunteers. All the eight CGIs (core region of p16, noncore regions of p16 and THBD; core regions of LOX, HRASLS, FLNc, and HAND1; and p41ARC exonic CGI) showed significantly elevated methylation levels (5.4- to 303-fold) in the H. pylori-positive volunteers. Methylation levels in the corpus were at the same levels as those in the antrum (taken with permission from [61]).
Mentions: DNA methylation is an important event in the regulation of gene expression, affecting all of the pathways in the cellular network [55]. DNA methylation is a process in which cytosines acquire a methyl group in 5′-position only if they are followed by a guanine (CpG site) [56]. This modification results in gene silencing. In this scenario, an emerging catalog of gastric cancer genes altered by DNA methylation has been established [10]. However, there are limited reports addressing the role of DNA methylation in the gastric precancerous cascade. Two studies [57, 58] demonstrated that IM showed a higher methylation index than that of AG, but no differences between IM and dysplasia were observed. Specific genes, such as p16, display up to a 4-fold increase in their methylation status in the progression from dysplasia to gastric cancer. A study by Chan et al. [59] demonstrated that DNA methylation of the CDH-1 gene was associated with H. pylori infection (p = 0.002) [59]. This study, alongside another manuscript by Leung et al. [60] evaluated the presence of DNA methylation in the CDH-1 promoter region before and after eradication of H. pylori. Results from both studies suggest that H. pylori eradication therapy may reverse aberrant DNA methylation in patients with AG. A significant reduction in the methylation density of the promoter region of the CDH-1 gene was also observed [60]. Maekita et al. [61] expanded these findings to other genes in a healthy donor population. Methylation levels were 5.4- to 303-fold higher in H. pylori-positive than in H. pylori-negative subjects (p < 0.0001) (Figure 2). Schneider et al. [62] performed a quantitative analysis of the DNA methylation status of the promoter region of Reprimo (RPRM), a putative tumor suppressor gene in gastric cancer [63], which demonstrated an association of the methylation status of the gene with the presence of virulence factors in the infecting H. pylori strains. Taken together, these findings suggest that H. pylori infection potently induces aberrant DNA methylation. Moreover, DNA methylation not only is induced by H. pylori infection, but also can be reversed by eradication therapy. In other words, aberrant DNA methylation may be considered to explain how environmental factors increase the susceptibility for cancer development [64]. An emerging body of evidence suggests that DNA methylation may be used as novel and specific biomarkers in gastric cancer [65, 66] through the measurement of circulating DNA in serum (cell-free DNA (cfDNA)). In this scenario, we have discovered that RPRM displays differences in methylation levels between nontumor adjacent mucosa (NTAM) and cancer tissue samples (Figure 3(a)) [63]. Methylation status of this gene may be assessed in plasma samples (Figure 3(b)) [67, 68], offering the opportunity for noninvasive detection of gastric cancer. Data presented here suggest that DNA methylation is a good example of how noncoding genomics not only participate in the pathogenesis of gastric cancer but also are a promising family of biomarkers for gastric cancer risk prediction and prognostication. Further validation of candidate methylation markers in independent cohorts will be required to translate to clinical applications.

Bottom Line: The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics.Noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics.Potential biomarkers are appearing from analyses of noncoding genomics.

View Article: PubMed Central - PubMed

Affiliation: Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, 8330034 Santiago, Chile ; Scientific and Technological Bioresource Nucleus (BIOREN) and Graduate Program in Applied Cell and Molecular Biology, Universidad de La Frontera, 4811230 Temuco, Chile ; UC-Center for Investigational Oncology (CITO), Pontificia Universidad Católica de Chile, 8330034 Santiago, Chile.

ABSTRACT
Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death, whose patterns vary among geographical regions and ethnicities. It is a multifactorial disease, and its development depends on infection by Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), host genetic factors, and environmental factors. The heterogeneity of the disease has begun to be unraveled by a comprehensive mutational evaluation of primary tumors. The low-abundance of mutations suggests that other mechanisms participate in the evolution of the disease, such as those found through analyses of noncoding genomics. Noncoding genomics includes single nucleotide polymorphisms (SNPs), regulation of gene expression through DNA methylation of promoter sites, miRNAs, other noncoding RNAs in regulatory regions, and other topics. These processes and molecules ultimately control gene expression. Potential biomarkers are appearing from analyses of noncoding genomics. This review focuses on noncoding genomics and potential biomarkers in the context of gastric cancer and the gastric precancerous cascade.

No MeSH data available.


Related in: MedlinePlus