Detection of p53 mutations in precancerous gastric tissue.
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ABSTRACT:
SUBMITTER: Morgan C
PROVIDER: S-EPMC2394306 | biostudies-other | 2003 Oct
REPOSITORIES: biostudies-other
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Project description:The most common histological type of gastric cancer (GC) is gastric adenocarcinoma arising from the gastric epithelium. Less common variants include mesenchymal, lymphoproliferative and neuroendocrine neoplasms. The Lauren scheme classifies GC into intestinal type, diffuse type and mixed type. The WHO classification includes papillary, tubular, mucinous, poorly cohesive and mixed GC. Chronic atrophic gastritis (CAG) and intestinal metaplasia are recommended as common precancerous conditions. No definite precancerous condition of diffuse/poorly/undifferentiated type is recommended. Chronic superficial inflammation and hyperplasia of foveolar cells may be the focus. Presently, the management of early GC and precancerous conditions mainly relies on endoscopy including diagnosis, treatment and surveillance. Management of precancerous conditions promotes the early detection and treatment of early GC, and even prevent the occurrence of GC. In the review, precancerous conditions including CAG, metaplasia, foveolar hyperplasia and gastric hyperplastic polyps derived from the gastric epithelium have been concluded, based on the overview of gastric epithelial histological organization and its renewal.
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Project description:ObjectiveMicrobial infections have been shown to contribute to gastric carcinogenesis, the knowledge of gastric microbiota alteration in this process may provide help in early diagnosis of gastric cancer. The aim of this study was to characterize the microbial changes and identify taxonomic biomarkers across stages of gastric carcinogenesis.MethodsThe gastric microbiota was investigated by 16S rRNA gene analysis in gastric mucosal specimens from 47 patients including superficial gastritis (SG), atrophic gastritis (AG), gastric intraepithelial neoplasia (GIN), and gastric cancer (GC). Differences in microbial composition across the disease stages, especially in GIN and GC were assessed using linear discriminant analysis effect size.ResultsThere was no gradual changing trend in the richness or diversity of the gastric microbiota across stages of gastric carcinogenesis. The relative abundance of dominant taxa at phylum and genus levels didn't show a gradual shift pattern, and the only four taxa that continuously enriched from SG to GC were Slackia, Selenomonas, Bergeyella, and Capnocytophaga, all of which were oral bacteria. The most representative taxa which were enriched in GC patients were oral bacteria including Parvimonas, Eikenella and Prevotella-2, and environmental bacteria including Kroppenstedtia, Lentibacillus, and Oceanobacillus. The gastric microbiota in GIN patients were characterized by enrichment of intestinal commensals including Romboutsia, Fusicatenibacter, Prevotellaceae-Ga6A1-group, and Intestinimonas. Gastric cardia cancer and non-cardia cancer patients had significantly different microbiota profiles characterized by a higher abundance of Helicobacter in the cardia cancer patients.ConclusionsOur results provide insights on potential taxonomic biomarkers for gastric cancer and precancerous stages, and suggest that gastric microbiota might play different roles in the carcinogenesis of cardia cancer and non-cardia cancer.
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Project description:AimTo observe the curative effect of Weiansan (WAS) on gastric precancerous lesions (GPL) and H pylori elimination.MethodsSeventy-six patients with GPL were randomly divided into two groups: WAS group (n = 42) and Weifuchun (WFC) group (n = 34). The patients in the WAS group were administered 5 g WAS 3 times a day, and the patients in the WFC group took WFC (4 tablets) 3 times a day. To monitor inflammation of gastric mucosa, degree of glandular atrophy (GA), intestinal metaplasia (IM) and dysplasia, and H pylori infection, all patients underwent gastroscopy and biopsy with pathological examination before and after treatment. Fifty male Sprague-Dawley (SD) rats were used in animal experiments. Of these, 10 served as the control group (n = 10), 40 were given ranitidine combined with N-methyl-N(1)-nitro-N-nitrosoguanidine (MNNG) for 12 wk and divided into 4 groups randomly: model group (n = 10), high-dose WAS group (n = 10), low-dose WAS group (n = 10) and WFC group (n = 10). Twelve weeks later, all rats were killed and a 2 cm multiply 1 cm tissue was taken from the lesser curvature of the gastric antrum. H pylori infection was determined by the fast urease method.ResultsThe curative effect in WAS groups was similar to that in WFC groups. There was no statistical difference in degree of GA, IM and dysplasia between WAS and WFC groups. The rate of H pylori infection in the model group (positive/negative: 9/1) was significantly higher than that in the control group (positive/negative: 1/9) (P < 0.01). H pylori elimination in the high-dose WAS group (positive/negative: 4/6) and low-dose WAS group (positive/negative: 6/4) was similar to that in the WFC group (positive/negative: 4/6) (P > 0.05).ConclusionWAS improves clinical symptoms by suppressing GA, IM and dysplasia and eliminating H pylori.
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Project description:Although recent studies have suggested that tooth loss is positively related to the risk of gastric non-cardia cancer, the underlying oral health conditions potentially responsible for the association remain unknown. We investigated whether clinical and behavioral measures of oral health are associated with the risk of gastric precancerous lesions. We conducted a cross-sectional study of 131 patients undergoing upper gastrointestinal endoscopy. Cases were defined as those with gastric precancerous lesions including intestinal metaplasia or chronic atrophic gastritis on the basis of standard biopsy review. A validated structured questionnaire was administered to obtain information on oral health behaviors. A comprehensive clinical oral health examination was performed on a subset of 91 patients to evaluate for periodontal disease and dental caries experience. A total of 41 (31%) cases of gastric precancerous lesions were identified. Compared with non-cases, cases were significantly more likely to not floss their teeth [odds ratio (OR) = 2.89, 95% confidence interval (CI): 1.09-7.64], adjusting for age, sex, race, body mass index, smoking status, educational attainment and Helicobacter pylori status in serum. Among participants who completed the oral examination, cases (n = 28) were more likely to have a higher percentage of sites with gingival bleeding than non-cases [OR = 2.63, 95% CI: 1.37-5.05 for a standard deviation increase in bleeding sites (equivalent to 19.7%)], independent of potential confounders. Our findings demonstrate that specific oral health conditions and behaviors such as gingival bleeding and tooth flossing are associated with gastric precancerous lesions.
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Project description:ObjectiveTo investigate whether microsatellite instability (MSI) of gastric cancer and precancerous lesions were existed and its effect.MethodsLaser microdissection was used. Gastric, intestinal metaplasia, dysplasia and normal mucosa were collected respectively. Five microsatellite loci were selected and MSI was detected by denaturing high-performance liquid chromatography.ResultsIn the five microsatellite loci REF-positive phenotype, intestinal metaplasia MSI was 20.7%. Dysplasia MSI was 22.4%. Gastric MSI was 47.9%, and there was no MSI in normal gastric mucosa.ConclusionMSI gradually increased from precancerous lesions to gastric cancer. The early detection of MSI may be a potential early warning indicator for early diagnosis of gastric cancer.
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Project description:Aging human tissues, such as sun-exposed epidermis, accumulate a high burden of progenitor cells that carry oncogenic mutations. However, most progenitors carrying such mutations colonize and persist in normal tissue without forming tumors. Here, we investigated tissue-level constraints on clonal progenitor behavior by inducing a single-allele p53 mutation (Trp53R245W; p53∗/wt), prevalent in normal human epidermis and squamous cell carcinoma, in transgenic mouse epidermis. p53∗/wt progenitors initially outcompeted wild-type cells due to enhanced proliferation, but subsequently reverted toward normal dynamics and homeostasis. Physiological doses of UV light accelerated short-term expansion of p53∗/wt clones, but their frequency decreased with protracted irradiation, possibly due to displacement by UV-induced mutant clones with higher competitive fitness. These results suggest multiple mechanisms restrain the proliferation of p53∗/wt progenitors, thereby maintaining epidermal integrity.
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Project description:Importance:Deep learning-based methods, such as the sliding window approach for cropped-image classification and heuristic aggregation for whole-slide inference, for analyzing histological patterns in high-resolution microscopy images have shown promising results. These approaches, however, require a laborious annotation process and are fragmented. Objective:To evaluate a novel deep learning method that uses tissue-level annotations for high-resolution histological image analysis for Barrett esophagus (BE) and esophageal adenocarcinoma detection. Design, Setting, and Participants:This diagnostic study collected deidentified high-resolution histological images (N?=?379) for training a new model composed of a convolutional neural network and a grid-based attention network. Histological images of patients who underwent endoscopic esophagus and gastroesophageal junction mucosal biopsy between January 1, 2016, and December 31, 2018, at Dartmouth-Hitchcock Medical Center (Lebanon, New Hampshire) were collected. Main Outcomes and Measures:The model was evaluated on an independent testing set of 123 histological images with 4 classes: normal, BE-no-dysplasia, BE-with-dysplasia, and adenocarcinoma. Performance of this model was measured and compared with that of the current state-of-the-art sliding window approach using the following standard machine learning metrics: accuracy, recall, precision, and F1 score. Results:Of the independent testing set of 123 histological images, 30 (24.4%) were in the BE-no-dysplasia class, 14 (11.4%) in the BE-with-dysplasia class, 21 (17.1%) in the adenocarcinoma class, and 58 (47.2%) in the normal class. Classification accuracies of the proposed model were 0.85 (95% CI, 0.81-0.90) for the BE-no-dysplasia class, 0.89 (95% CI, 0.84-0.92) for the BE-with-dysplasia class, and 0.88 (95% CI, 0.84-0.92) for the adenocarcinoma class. The proposed model achieved a mean accuracy of 0.83 (95% CI, 0.80-0.86) and marginally outperformed the sliding window approach on the same testing set. The F1 scores of the attention-based model were at least 8% higher for each class compared with the sliding window approach: 0.68 (95% CI, 0.61-0.75) vs 0.61 (95% CI, 0.53-0.68) for the normal class, 0.72 (95% CI, 0.63-0.80) vs 0.58 (95% CI, 0.45-0.69) for the BE-no-dysplasia class, 0.30 (95% CI, 0.11-0.48) vs 0.22 (95% CI, 0.11-0.33) for the BE-with-dysplasia class, and 0.67 (95% CI, 0.54-0.77) vs 0.58 (95% CI, 0.44-0.70) for the adenocarcinoma class. However, this outperformance was not statistically significant. Conclusions and Relevance:Results of this study suggest that the proposed attention-based deep neural network framework for BE and esophageal adenocarcinoma detection is important because it is based solely on tissue-level annotations, unlike existing methods that are based on regions of interest. This new model is expected to open avenues for applying deep learning to digital pathology.
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Project description:We try to explore the value of aberrant DNA methylation of several cancer-related genes in plasma as non-invasive biomarkers for gastric cancer (GC) and precancerous lesions. By using methylation-specific polymerase chain reaction assay we determined the methylation status of three selected genes ZIC1, HOXD10 and RUNX3 in blood samples from patients with GC and precancerous lesions. We discovered that the methylation rate of ZIC1, HOXD10 and RUNX3 increased significantly in the progression of gastric carcinogenesis. Methylation of ZIC1 was associated with positive serum CA19-9, while that of HOXD10 was related to H. pylori status, serum CA19-9 and CEA levels and tumor invasion depth. The Odds ratios (ORs) of ZIC1, HOXD10 and RUNX3 methylation for predicting GC were 4.285 (95%CI: 2.435-7.542), 3.133 (95%CI: 1.700-5.775) and 2.674 (95%CI: 1.441-4.960), while for predicting "gastric cancer and intraepithelial neoplasia" (GnI), the ORs were 12.011 (95%CI: 0.050-28.564), 9.174 (95%CI: 3.220-26.135) and 12.794 (95%CI: 4.115-39.778), respectively. In terms of combined detection of these three genes, the sensitivity was 91.6% for GC and 89.8% for GnI, with the highest Youden index in both GC and GnI determination. Conclusively, combined detection of ZIC1, HOXD10 and RUNX3 promoter hypermethylation might be a promising strategy for early detection of GC and precancerous lesions.
| S-EPMC5436257 | biostudies-literature
Project description: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.
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Project description:We examined whether colonization of selected oral pathogens is associated with gastric precancerous lesions in a cross-sectional study. A total of 119 participants were included, of which 37 were cases of chronic atrophic gastritis, intestinal metaplasia, or dysplasia. An oral examination was performed to measure periodontal indices. Plaque and saliva samples were tested with real-time quantitative PCR for DNA levels of pathogens related to periodontal disease (Porphyromonas gingivalis, Tannerella forsythensis, Treponema denticola, Actinobacillus actinomycetemcomitans) and dental caries (Streptococcus mutans and S. sobrinus). There were no consistent associations between DNA levels of selected bacterial species and gastric precancerous lesions, although an elevated but non-significant odds ratio (OR) for gastric precancerous lesions was observed in relation to increasing colonization of A. actinomycetemcomitans (OR = 1.36 for one standard deviation increase, 95% Confidence Interval = 0.87-2.12), P. gingivalis (OR = 1.12, 0.67-1.88) and T. denticola (OR = 1.34, 0.83-2.12) measured in plaque. To assess the influence of specific long-term infection, stratified analyses by levels of periodontal indices were conducted. A. actinomycetemcomitans was significantly associated with gastric precancerous lesions (OR = 2.51, 1.13-5.56) among those with ? median of percent tooth sites with PD ? 3 mm, compared with no association among those below the median (OR = 0.86, 0.43-1.72). A significantly stronger relationship was observed between the cumulative bacterial burden score of periodontal disease-related pathogens and gastric precancerous lesions among those with higher versus lower levels of periodontal disease indices (p-values for interactions: 0.03-0.06). Among individuals with periodontal disease, high levels of colonization of periodontal pathogens are associated with an increased risk of gastric precancerous lesions.
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