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Project description:HKU Gastric Intestinal Metaplasia study: Single-cell RNA sequencing, transcriptome and methylation profiling
| PRJNA868480 | ENA
Project description:BackgroundMeasuring the DNA methylome may offer the opportunity to identify novel disease biomarkers and insights into disease mechanisms. Although aberrant DNA methylation has been investigated in many human cancers and precancerous lesions, the DNA methylation landscape of gastric cardiac intestinal metaplasia (IM) remains unknown. Therefore, we aimed to investigate the genome-wide DNA methylation landscape and to search for potential epigenetic biomarkers of gastric cardiac IM.MethodsHistopathologic profiling was performed on a total of 118 gastric cardiac biopsies from cancer-free individuals. Genome-wide DNA methylation analysis was performed on 11 gastric cardiac mucosal biopsies (IM = 7; normal = 4) using Illumina 850K microarrays. Transcriptional relevance of any candidate epigenetic biomarker was validated by qRT-PCR.ResultsThe detection rate of gastric cardiac IM was 23% (27/118) in cancer-free individuals. Genome-wide DNA methylation profiling showed a global decrease in methylation in IM compared with normal tissues (median methylation = 0.64 and 0.70 for gastric cardiac IM and normal tissues, respectively). Differential methylation analysis between gastric cardiac IM and normal tissues identified 38,237 differentially methylated probes (DMPs) with a majority of sites showing hypermethylation in IM compared with normal tissues (56.3% vs. 43.7%). Subsequent analysis revealed a significant enrichment of hypermethylated DMPs in promoter and CpG islands (p < 0.001 for both, Pearson χ2 test). For DMPs located in promoter CpG islands showing extreme hypermethylation, the candidate gene with the largest number of DMPs (n = 7) was mapped to HOXA5. Accordingly, mRNA expression of HOXA5 was significantly reduced in IM compared to normal tissue.ConclusionsOur results suggest the implication of alterations in DNA methylation in gastric cardiac IM and highlight that HOXA5 hypermethylation may be a promising epigenetic biomarker, emphasizing the role of aberrant HOXA5 expression in the pathogenesis of gastric cardiac IM.
| S-EPMC7393819 | biostudies-literature
Project description:Intestinal metaplasia in the esophagus (Barrett's esophagus IM, or BE-IM) and stomach (GIM) are considered precursors for esophageal and gastric adenocarcinoma, respectively. We hypothesize that BE-IM and GIM follow parallel developmental trajectories in response to differing inflammatory insults. Here, we construct a single-cell RNA-sequencing atlas, supported by protein expression studies, of the entire gastrointestinal tract spanning physiologically normal and pathologic states including gastric metaplasia in the esophagus (E-GM), BE-IM, atrophic gastritis, and GIM. We demonstrate that BE-IM and GIM share molecular features, and individual cells simultaneously possess transcriptional properties of gastric and intestinal epithelia, suggesting phenotypic mosaicism. Transcriptionally E-GM resembles atrophic gastritis; genetically, it is clonal and has a lower mutational burden than BE-IM. Finally, we show that GIM and BE-IM acquire a protumorigenic, activated fibroblast microenvironment. These findings suggest that BE-IM and GIM can be considered molecularly similar entities in adjacent organs, opening the path for shared detection and treatment strategies.SignificanceOur data capture the gradual molecular and phenotypic transition from a gastric to intestinal phenotype (IM) in the esophagus and stomach. Because BE-IM and GIM can predispose to cancer, this new understanding of a common developmental trajectory could pave the way for a more unified approach to detection and treatment. See related commentary by Stachler, p. 1291. This article is highlighted in the In This Issue feature, p. 1275.
| S-EPMC10236154 | biostudies-literature
Project description:Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception.
| S-EPMC10729843 | biostudies-literature
Project description:Gastric cancer (GC) remains one of the most common causes of mortality worldwide. Intestinal metaplasia (IM) is one of the preneoplastic gastric lesions and is considered an essential predisposing factor in GC development. Here we present a review of recent most relevant papers to summarize major findings on the molecular alterations in gastric IM. The latest progress in novel diagnostic methods allows scientists to identify various types of molecular alterations in IM, such as polymorphisms in various genes, changes in the expression of micro-RNAs and long noncoding RNAs, and altered microbiome profiles. The results have shown that some of these alterations have strong associations with IM and a potential to be used for screening, treatment, and prognostic purposes; however, one of the most important limiting factors is the inhomogeneity of the studies. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As of today, various molecular alterations in IM could become a part of personalized medicine in the near future, which would help us deliver a personalized approach for each patient and identify those at risk of progression to GC.
| S-EPMC8199079 | biostudies-literature
Project description:Gene silencing by methylation of promoter CpG islands is deeply involved in cancers, but its involvement in polyclonal disorders is still unclear. Here, we analyzed the presence of gene silencing in intestinal metaplasia (IM) of the stomach, a polyclonal disorder, in which multiple gastric glands aberrantly differentiate into those with intestinal characteristics. By a genome-wide screening, CpG islands in the putative promoter regions of four genes (ZIK1, ZNF141, KAL1, and FGF14) were found to be specifically methylated in glands with IM, and their expression was markedly decreased. When demethylation was induced in cell lines with their methylation by 5-aza-2'-deoxycytidine, expression of ZIK1, KAL1, and FGF14 was restored, supporting causal roles of methylation in their silencing. Analysis of ZIK1 methylation in a single gland showed that the vast majority of DNA molecules isolated from a gland with IM were methylated and that those from a gland without IM were not. ZIK1 methylation was present in glands isolated from physically distant positions within a stomach, showing that methylation occurred multifocally. These data indicate that methylation of multiple genes occurs independently in multiple glands, each of which has its own stem cell, demonstrating that involvement of aberrant gene silencing in noninherited polyclonal human disorders needs more attention.
| S-EPMC1780214 | biostudies-literature
Project description:Evidence suggests that Helicobacter pylori plays a role in gastric cancer (GC) initiation. However, epidemiologic studies on the specific role of other bacteria in the development of GC are lacking. We conducted a case-control study of 89 cases with gastric intestinal metaplasia (IM) and 89 matched controls who underwent upper gastrointestinal endoscopy at three sites affiliated with NYU Langone Health. We performed shotgun metagenomic sequencing using oral wash samples from 89 case-control pairs and antral mucosal brushing samples from 55 case-control pairs. We examined the associations of relative abundances of bacterial taxa and functional pathways with IM using conditional logistic regression with and without elastic-net penalty. Compared with controls, oral species Peptostreptococcus stomatis, Johnsonella ignava, Neisseria elongata and Neisseria flavescens were enriched in cases (odds ratios [ORs] = 1.29-1.50, P = .004-.01) while Lactobacillus gasseri, Streptococcus mutans, S parasanguinis and S sanguinis were under-represented (ORs = 0.66-0.76, P = .006-.042) in cases. Species J ignava and Filifactor alocis in the gastric microbiota were enriched (ORs = 3.27 and 1.43, P = .005 and .035, respectively), while S mutans, S parasanguinis and S sanguinis were under-represented (ORs = 0.61-0.75, P = .024-.046), in cases compared with controls. The lipopolysaccharide and ubiquinol biosynthesis pathways were more abundant in IM, while the sugar degradation pathways were under-represented in IM. The findings suggest potential roles of certain oral and gastric microbiota, which are correlated with regulation of pathways associated with inflammation, in the development of gastric precancerous lesions.
| S-EPMC8770574 | biostudies-literature
Project description:Unpublished single cell RNAseq data from pan-GI integration study from healthy adult donors (20-70 years old; stomach, duodenum, ileum) and control samples from preterm infants (23-31 PCW; small intestine and colon). Details for sample processing can be found in the manuscript.
2024-11-21 | E-MTAB-14050 | biostudies-arrayexpress
Project description:BackgroundAs a precursor to gastric cancer, gastric intestinal metaplasia (GIM) represents a target for surveillance. US-based guidelines recommend surveillance of racial/ethnic minorities and immigrants from high incidence gastric cancer regions, yet there is marked variability in prevalence amongst these subgroups and within groups from high incidence regions. There is a paucity of information regarding country of birth as a risk factor for GIM and we sought to determine the association between country of birth and GIM in an ethnically and racially diverse US population.MethodsThis was a retrospective cohort study of persons who underwent esophagogastroduodenoscopy (EGD) with gastric biopsy at University of Miami Hospital between 2011 and 2021. A natural language processing (NLP) algorithm was developed and implemented to extract diagnoses of GIM and Helicobacter pylori (HP) infection from endoscopic pathology reports. Multivariable logistic regression was performed to evaluate risk factors for GIM, accounting for important covariates, including country of birth.FindingsA total of 21,108 persons from 130 varying countries of birth were included in the study. A total of 1699 cases of GIM were identified yielding a prevalence of 8.0% (95% CI: 7.7-8.4%). Multivariable analysis was restricted to countries with at least 100 persons in the cohort, yielding 15 countries with 1208 cases of GIM. Country of birth (p < 0.0001), race/ethnicity (p = 0.026), active HP infection (p < 0.0001), and increasing age (p < 0.0001) were significantly associated with increased odds of GIM. Highest odds for GIM were among persons born in Ecuador (OR 2.34, 95% CI 1.56-3.50), Honduras (OR 2.34, 95% CI 1.65-3.34), and Peru (OR 2.17, 95% CI 1.58-2.99).InterpretationWe demonstrate that country of birth is a key risk factor for GIM. Not all countries that are thought to be in "high-risk" regions are associated with higher rates of GIM, underlining the importance of studying the under-investigated risk factor of country of birth. Guidelines should account for country of birth, in addition to other risk factors, to tailor screening/surveillance appropriately.FundingShida Haghighat, MD, MPH is supported by an NIH training grant T32 DK 11667805.
| S-EPMC10711156 | biostudies-literature
Project description:BackgroundIntestinal metaplasia (IM) is considered a key pivot point in the Correa model of gastric cancer (GC). It is histologically subtyped into the complete and incomplete subtypes, the latter being associated with a greater risk of progression. However, the clinical utility of IM subtyping remains unclear, partially due to the absence of reliable defining biomarkers.MethodsBased on gene expression data and existing literature, we selected CD10 and Das1 as candidate biomarkers to distinguish complete and incomplete IM glands in tissues from patients without GC (IM-GC) and patients with GC (IM + GC). Immunohistochemical staining of individually subtyped IM glands was scored after blinding by two researchers using tissue belonging to both IM-GC and IM + GC patients. Whole tissue Das1 staining was further assessed using digital image quantification (cellSens Dimension, Olympus).ResultsAcross both cohorts CD10 stained the IM brush border and was shown to have a high sensitivity (87.5% and 94.9% in IM-GC and IM + GC patients respectively) and specificity (100.0% and 96.7% respectively) with an overall AUROC of 0.944 for complete IM glands. By contrast Das1 stained mainly goblet cells and the apical membrane of epithelial cells, mostly of incomplete IM glands with a low sensitivity (28.6% and 29.3% in IM-GC and IM + GC patients respectively) but high specificity (98.3% and 85.1% respectively) and an overall AUROC of 0.603 for incomplete IM glands. A combined logistic regression model showed a significant increase in AUROC for detecting complete IM glands (0.955 vs 0.970). Whole tissue digital quantification of Das1 staining showed a significant association with incomplete IM compared to complete IM, both in IM-GC and in IM + GC patients (p = 0.016 and p = 0.009 respectively, Mann-Whitney test and unpaired t test used). Additionally, complete IM in IM + GC patients exhibited significantly more Das1 staining than in IM-GC patients (p = 0.019, Mann-Whitney test).ConclusionsThese findings suggest that CD10 is an outstanding biomarker for complete IM and Das1 may be useful as a secondary biomarker for IM glands at greater risk of progression irrespective of IM subtype. Overall, the clinical use of these biomarkers could lead to improved patient stratification and targeted surveillance.
| S-EPMC9026694 | biostudies-literature