Abstract
Simple SummaryIntestinal 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.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.
Highlights
Gastric cancer remains the third leading cause worldwide of cancer death in men and the fifth leading cause in women [1]
We studied the CpG methylation profiles in tumor/adjacent non-tumor paired samples from patients with primary gastric adenocarcinoma classified as an intestinal subtype (n = 13) and diffuse subtype (n = 11)
We focused on hypermethylation events because it is well known that epigenetic silencing of relevant genes by a gain of CpG methylation in regulatory regions is a hallmark of cancer [8], and in addition, we ascertained that a gain of methylation in the intestinal type of gastric cancer was most frequent in regulatory sequences (Figure 1B)
Summary
Gastric cancer remains the third leading cause worldwide of cancer death in men and the fifth leading cause in women [1]. The main strategies in gastric cancer management are first, prevention, i.e., the identification of individuals at the highest risk of cancer initiation, and second, early diagnosis [3]. The first alteration in the gastric mucosa is characterized by an active chronic inflammation that can progress to multifocal chronic atrophic gastritis (CAG). CAG is considered the first step in the precancerous cascade that can sequentially progress to intestinal metaplasia (IM; complete or incomplete subtype), dysplasia (low- or high-grade) and, invasive gastric carcinoma. One of the main risk factors that drive the precancerous cascade by initiating the first lesion or non-atrophic gastritis (NAG) [6] is Helicobacter pylori (H. pylori) infection, and pharmacological eradication of the bacterium in infected patients is one of the most effective prevention strategies in gastric cancer.
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