Human gastric cancer risk screening: From rat pepsinogen studies to the ABC method.
ABSTRACT: We examined the development of gastric cancer risk screening, from rat pepsinogen studies in an experimental rat gastric carcinogenesis model induced with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and human pepsinogen studies in the 1970s and 1980s to the recent "ABC method" for human gastric cancer risk screening. First, decreased expression or absence of a major pepsinogen isozyme, PG1, was observed in the rat gastric mucosa from the early stages of gastric carcinogenesis to adenocarcinomas following treatment with MNNG. In the 1980s, decreases in PGI in the human gastric mucosa and serum were identified as markers of atrophic gastritis. In the 1990s, other researchers revealed that chronic infection with Helicobacter pylori (Hp) causes atrophic gastritis and later gastric cancer. In the 2000s, a gastric cancer risk screening method combining assays to detect serum anti-Hp IgG antibody and serum PGI and PGII levels, the "ABC method", was established. Eradication of Hp and endoscopic follow-up examination after the ABC method are recommended to prevent gastric cancer.
Project description:BACKGROUND/AIMS: The characteristics of pepsinogen screening for gastric cancer were investigated to establish a suitable cut off point for identifying gastric cancer, using endoscopic diagnosis as the yardstick. SUBJECTS/METHODS: Serum pepsinogen concentrations were measured in 5113 subjects who were also screened for gastric cancer by endoscopy. The cut off point for pepsinogen was determined using receiver operator characteristics curves. RESULTS: The most suitable cut off point was a pepsinogen I concentration of less than 70 ng/ml and a ratio of pepsinogen I to pepsinogen II of less than 3. 0. Using this cut off point, the sensitivity and specificity of pepsinogen screening for gastric cancer were 84.6% and 73.5% respectively. All cases of gastric cancer in patients with severe atrophic gastritis were detected. However, two of four cases of gastric cancer in patients with mild atrophic gastritis were overlooked. In subjects with mild atrophic gastritis, when gastric cancer arises within the fundic gland region, the size of the lesion determines whether it is possible to detect cancer by serum pepsinogen screening. CONCLUSION: Pepsinogen screening has many advantages, including its suitability for combination with other screening methods because it is simple and inexpensive.
Project description:<h4>Background</h4>Pepsinogens (PGs) can be used for gastric cancer (GC) screening, but the cutoff levels vary among studies, and PG levels are influenced by numerous factors. The aim of this article is to examine the diagnostic value of PG levels and Helicobacter pylori (Hp) status for GC and atrophic gastritis screening in asymptomatic individuals undergoing health checkup in China.<h4>Patients and methods</h4>This was a multicenter cross-sectional study of subjects who underwent health checkup from 10/2016 to 10/2018 at nine International Healthcare Centers in China. All participants underwent gastroscopy and pathological examination, serum PG, <sup>13</sup>C-urea breath test, and/or <i>Hp</i> serological current infection marker rapid test, all on the same day. PG-related parameters were analyzed in different <i>Hp</i> subgroups and regions.<h4>Results</h4>The patients were grouped as non-atrophic (NAG, n = 1,590), mild to moderate atrophic (MAG, n = 273), severe atrophic (SAG, n = 49), and GC (n = 10). The serum PG levels in these groups decreased with increasing pathological severity. In the same pathological groups, PGI and PGII levels were higher in the <i>Hp</i>-positive subgroup, while PGR (PGI/PGII ratio) was lower (P < 0.05). The best cutoff values for atrophy diagnosis were PGI ≤73.1 ng/ml and PGR ≤9.8, for severe atrophy were PGI ≤63.9 ng/ml and PGR ≤9.09, and for GC was PGR ≤4.7 (all P < 0.05 and area under the curve >0.7). The cutoff points varied with <i>Hp</i> status and China regions.<h4>Conclusion</h4>Serum PG levels might be used for the screening of gastric atrophic gastritis lesions. The results suggest that different cutoff values should possibly be used in different <i>Hp</i> status groups and geographical regions, but it will have to be validated in future studies. Future studies should also examine the value of PG levels for GC detection.
Project description:Serum pepsinogens have been widely acknowledged as gastric mucosal biomarkers; however, a multicountry report on the benefits of pepsinogens as biomarkers has not yet been published. We analyzed 1,206 sera and gastric mucosal samples collected from Bangladesh, Bhutan, Indonesia, Myanmar, Nepal and Thailand then assessed the association between gastric mucosal changes and Helicobacter pylori infection. The new cutoff values for serum pepsinogen values were evaluated using a receiver operating characteristic analysis. The participants with H. pylori infection had significantly lower pepsinogen I and higher pepsinogen II values, but a lower pepsinogen I/II ratio than participants without the infection (all P < .001). The pepsinogen I and pepsinogen I/II values were significantly higher and lower, respectively, in individuals with atrophic gastritis than in those without (both P < .001). Among uninfected individuals, only the pepsinogen I/II ratio was significantly lower in atrophic individuals. Pepsinogen I/II ratio also were significantly different between disease among H. pylori-positive and H. pylori-negative individuals, suggesting the pepsinogen I/II ratio is a robust biomarker for determining both chronic and atrophic gastritis. The cutoffs for detecting chronic and atrophic gastritis for the pepsinogen I/II ratio were 4.65 and 4.95, respectively. In conclusion, pepsinogen levels are useful biomarker for both chronic gastritis and atrophic gastritis, but they should be used with caution. Population-based validation is necessary to determine the best cutoff values. Among all pepsinogen values, the pepsinogen I/II ratio was the most reliable gastric mucosal-change biomarker.
Project description:BACKGROUND:The human upper digestive tract microbial community (microbiota) is not well characterized and few studies have explored how it relates to human health. We examined the relationship between upper digestive tract microbiota and two cancer-predisposing states, serum pepsinogen I/pepsinogen II ratio (PGI/II; predictor of gastric cancer risk) and esophageal squamous dysplasia (ESD; the precursor lesion of esophageal squamous cell carcinoma; ESCC) in a cross-sectional design. METHODS:The Human Oral Microbe Identification Microarray was used to test for the presence of 272 bacterial species in 333 upper digestive tract samples from a Chinese cancer screening cohort. Serum PGI and PGII were determined by ELISA. ESD was determined by chromoendoscopy with biopsy. RESULTS:Lower microbial richness (number of bacterial genera per sample) was significantly associated with lower PGI/II ratio (P = 0.034) and the presence of ESD (P = 0.018). We conducted principal component (PC) analysis on a ?-diversity matrix (pairwise difference in microbiota), and observed significant correlations between PC1, PC3, and PGI/II (P = 0.004 and 0.009, respectively), and between PC1 and ESD (P = 0.003). CONCLUSIONS:Lower microbial richness in upper digestive tract was independently associated with both cancer-predisposing states in the esophagus and stomach (presence of ESD and lower PGI/II). IMPACT:These novel findings suggest that the upper digestive tract microbiota may play a role in the etiology of chronic atrophic gastritis and ESD, and therefore in the development of gastric and esophageal cancers.
Project description:OBJECTIVE:Understanding the correlates of premalignant gastric lesions is essential for gastric cancer prevention. We examined the prevalence and correlates of serological evidence of atrophic gastritis, a premalignant gastric condition, using serum pepsinogens (PGs) in two populations with differing trends in gastric cancer incidence. METHODS:In a cross-sectional study, using ELISA we measured serum PGI and PGII concentrations (Biohit, Finland), Helicobacter pylori serum IgG and cytotoxin-associated gene A (CagA) antigen IgG antibodies in archived sera of 692 Jews and 952 Arabs aged 25-78 years, randomly selected from Israel's population registry in age-sex and population strata. Multivariable logistic regression analyses were performed. RESULTS:Using cut-offs of PGI <30µg/L ?or PGI:PGII <3.0, the prevalence of atrophic gastritis was higher among Arab than Jewish participants: 8.8% (95% CIs 7.2% to 10.8%) vs 5.9% (95% CI 4.4% to 7.9%), increasing with age in both groups (p<0.001 for trend). Among Jewish participants, infection with H. pylori CagA phenotype was positively related to atrophic gastritis: adjusted OR (aOR) 2.16 (95% CI 0.94 to 4.97), but not to non-CagA infections aOR 1.17 (95% CI 0.53 to 2.55). The opposite was found among Arabs: aOR 0.09 (95% CI 0.03 to 0.24) for CagA positive and aOR 0.15 (95% CI 0.06 to 0.41) for Cag A negative phenotypes (p<0.001 for interaction). Women had a higher atrophic gastritis prevalence than men. Obesity and smoking were not significantly related to atrophic gastritis; physical activity tended to be inversely associated in Arabs (p=0.08 for interaction). CONCLUSIONS:The prevalence of atrophic gastritis was higher among Arabs than Jews and was differently associated with the CagA phenotype.
Project description:INTRODUCTION:To prevent gastric cancer, it is important to accurately determine the presence of Helicobacter pylori (HP) infection. However, correctly identifying HP-uninfected individuals is difficult when using the combination of HP antibody and pepsinogen (PG). OBJECTIVE:The aim of this study was to discriminate true HP-uninfected individuals from others without the need for endoscopic examination. METHODS:A total of 684 subjects with no history of HP eradication who underwent a medical checkup at our hospital were enrolled. The "true uninfected individuals" were determined by a negative stool antigen test and no endoscopic findings of HP-associated gastritis. HP antibody was measured by the latex immunoassay method. Logistic regression analysis using a combination of noninvasive parameters was performed to develop a formula for predicting true uninfected individuals. RESULTS:A total of 528 subjects were classified as true uninfected individuals. Logistic regression analysis showed that statistically significant factors for true uninfected individuals were age (p < 0.001), HP antibody (p <0.001), PGI (p <0.001), and PGII (p = 0.012). The areas under the curve (AUCs) for true uninfected individuals were the highest (0.944) upon applying the prediction formula including four parameters: age, HP antibody, PGI, and PGII. Both the sensitivity and the specificity of the four-parameter prediction formula were higher than those of the traditional three-parameter model using HP antibody, PGI, and PGI/II ratio (sensitivity: 93.2% vs. 86.6% and specificity: 88.5% vs. 82.7%). CONCLUSIONS:Our findings suggest that a model with a combination of four noninvasive parameters is useful for predicting true HP-uninfected individuals without the need for endoscopic examination.
Project description:<h4>Background</h4>Whether the characteristics and prognosis of gastric cancer (GC) are different in patients with and without Helicobacter pylori (HP) remains controversial. The definitions of HP status in patients with atrophic gastritis but negative tests for HP are heterogeneous. We aimed to assess the impact of HP on the prognosis of GC using different definitions.<h4>Methods</h4>From 1998 Nov to 2011 Jul, five hundred and sixty-seven consecutive patients with GC were included. HP status was determined by serology and histology. Patients with any positive test were defined as HP infection. Patients without HP infection whose serum pepsinogen (PG) I <70 ng/dl and PG I/II ratio < 3.0 were defined as atrophic gastritis and they were categorized into model 1: HP positive; model 2: HP negative; and model 3: exclusion of these patients.<h4>Results</h4>We found four characteristics of HP negative GC in comparison to HP positive GC: (1) higher proportion of the proximal tumor location (24.0%, P = 0.004), (2) more diffuse histologic type (56.1%, p = 0.008), (3) younger disease onset (58.02 years, p = 0.008) and (4) more stage IV disease (40.6%, p = 0.03). Patients with negative HP had worse overall survival (24.0% vs. 35.8%, p = 0.035). In Cox regression models, the negative HP status is an independent poor prognostic factor (HR: 1.34, CI:1.04-1.71, p = 0.019) in model 1, especially in stage I, II and III patients (HR: 1.62; CI:1.05-2.51,p = 0.026).<h4>Conclusion</h4>We found the distinct characteristics of HP negative GC. The prognosis of HP negative GC was poor.
Project description:BACKGROUND:Helicobacter pylori (HP) infection and chronic atrophic gastritis (CAG) have shown strong associations with the development of gastric cancer. This study aimed to examine whether both risk factors are associated with accelerated epigenetic ageing, as determined by the 'DNA methylation age', in a population-based study of older adults (n=1477). METHODS:Serological measurements of HP antibodies and pepsinogen I and II for CAG definition were obtained by ELISA kits. Whole blood DNA methylation profiles were measured by Illumina Human Methylation450K Beadchip. DNA methylation ages were calculated by two algorithms proposed by Horvath and Hannum et al. RESULTS:After adjusting for potential covariates in linear regression models, we found that HP infection, infection with virulent HP strains (CagA+) and severe CAG were significantly associated with an increase in DNA methylation age by ?0.4, 0.6 and 1 year (all P-values <0.05), respectively. CONCLUSIONS:Our study indicates that both CagA+ HP infection and CAG go along with accelerated epigenetic ageing.
Project description:<h4>Background</h4>Pepsinogen C (PGC) plays an important role in sustaining the cellular differentiation during the process of gastric carcinogenesis. This study aimed to assess the role of PGC tagSNPs and their interactions with Helicobacter pylori (H. pylori) in the development of gastric cancer and its precursor, atrophic gastritis.<h4>Methods</h4>Four PGC tagSNPs (rs6941539, rs6912200, rs3789210 and rs6939861) were genotyped by Sequenom MassARRAY platform in a total of 2311 subjects consisting of 642 gastric cancer, 774 atrophic gastritis, and 895 healthy control subjects. The mRNA and protein expression levels of PGC in gastric tissues and in serum were respectively measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemistry, and Eenzyme-linked immunoabsorbent assay (ELISA).<h4>Results</h4>We found associations between PGC rs3789210 CG/GG genotypes and reduced gastric cancer risk and between PGC rs6939861 A variant allele and increased risks of both gastric cancer and atrophic gastritis. As for the haplotypes of PGC rs6941539-rs6912200-rs3789210-rs6939861 loci, the TTCA and TTGG haplotypes were respectively associated with increased and reduced risks of both gastric cancer and atrophic gastritis; additionally, the CTCA haplotype was associated with increased atrophic gastritis risk. Very interestingly, rs6912200 CT/TT genotypes had a positive interaction with H. pylori, synergistically elevating the gastric cancer risk. Moreover, healthy subjects who carried rs6912200 CT, TT and CT/TT variant genotypes had lower histological and serum expression levels of PGC protein.<h4>Conclusions</h4>Our findings highlight an important role of PGC rs3789210 and rs6939861 in altering susceptibility to atrophic gastritis and/or gastric cancer. Moreover, people who carry rs6912200 variant genotypes exhibit higher gastric cancer risk in case of getting H. pylori infection, which strongly suggest a necessity of preventing and/or eliminating H. pylori infection in those individuals.
Project description:BACKGROUND:This study aimed to explore the diagnostic value of serum miR-101-3p combined with pepsinogen (PG) on early diagnosis of gastric cancer (GC). METHODS:A total of 61 atrophic gastritis (AG) and 86 GC patients, and 50 healthy volunteers were enrolled. The serum expression of miR-101-3p was measured by qRT-PCR. The serum content of carcinoembryonic antigen (CEA) was measured by Electrochemiluminescence immunoassay. The serum contents of PGI and PGII were measured by Enzyme linked immunosorbent assay. The diagnostic value of serum markers on AG and GC was analyzed by receiver operating characteristic (ROC) analysis. RESULTS:The expression of miR-101-3p, the content of PGI and the ratio of PGI/II were significantly decreased, and the content of PGII was significantly increased in AG patients compared with those in normal controls. The changes of the above serum indicators were more obvious in GC patients than those in AG patients. The content of CEA was significantly higher in GC patients than that in AG patients. In addition, the expression of miR-101-3p was negatively associated with the submucosal infiltration in GC patients. MiR-101-3p exhibited high diagnostic value on AG (AUC 0.8493, sensitivity 80.33%, specificity 80%) and GC (AUC 0.8749, sensitivity 72.09%, specificity 86.49%). MiR-101-3p?+?PGI?+?PGI/II (AUC 0.856, sensitivity 80.23%, specificity 77.05%) exhibited a high diagnostic value in distinguishing between AG and GC. CONCLUSIONS:MiR-101-3p was a potential diagnostic marker for AG and GC. MiR-101-3p?+?PGI?+?PGI/II was effective in distinguishing between AG and GC.