BACKGROUND:Previous studies have suggested a possible association between Helicobacter pylori (H. pylori) infection and an increased risk of colorectal cancer (CRC). OBJECTIVE:We examined the associations of H. pylori infection and H. pylori treatment with incident CRC risk and evaluated whether these associations were modified by genetic susceptibility. DESIGN:This study was based on two randomised trial cohorts: the Shandong Intervention Trial (SIT; n=3365; 1995-2024) and the Mass Intervention Trial in Linqu, Shandong Province (MITS; n=180 284; 2011-2024). Within MITS, we further conducted a case-cohort study to assess CRC risk according to seropositivity for H. pylori virulence factors and host genetic predisposition. RESULTS:Compared with H. pylori-negative individuals, H. pylori-positive individuals who did not receive antibiotic treatment had a significantly higher risk of CRC (SIT: HR=2.96, 95% CI 1.30 to 6.71; MITS: HR=1.27, 95% CI 1.04 to 1.55). The increased risk was particularly evident among individuals seropositive for four H. pylori-specific antigens (CagA, HpaA, Omp and HP0305) and those at high genetic risk (top decile of the Polygenic Risk Score). In SIT, H. pylori treatment was associated with a significantly reduced CRC risk over 29.4 years of follow-up (HR=0.47, 95% CI 0.22 to 0.99), with a greater reduction observed among participants with successful eradication (HR=0.38, 95% CI 0.15 to 0.94). In MITS, no overall benefit was observed 13.8 years after treatment (HR=1.17, 95% CI 0.95 to 1.43). However, a protective effect was apparent among individuals at high genetic risk and among those seropositive for key H. pylori-specific antigens. CONCLUSION:In post hoc observational analyses of two established trial cohorts, H. pylori infection was associated with an increased risk of CRC. H. pylori treatment reduced CRC risk in SIT, whereas in MITS, the benefit appeared to be limited to individuals at high genetic risk or those infected with specific virulence factor subtypes.

Gastric cancer is a leading cause of cancer-related deaths in China. Affecting more than 40% of the world's population, Helicobacter pylori is a major risk factor for gastric cancer. While previous clinical trials indicated that eradication of H. pylori could reduce gastric cancer risk, this remains to be shown using a population-based approach. We conducted a community-based, cluster-randomized, controlled, superiority intervention trial in Linqu County, China, with individuals who tested positive for H. pylori using a C-13-urea breath test randomly assigned to receiving either (1) a 10-day, quadruple anti-H. pylori treatment (comprising 20 mg of omeprazole, 750 mg of tetracycline, 400 mg of metronidazole and 300 mg of bismuth citrate) or (2) symptom alleviation treatment with a single daily dosage of omeprazole and bismuth citrate. H. pylori-negative individuals did not receive any treatment. We examined the incidence of gastric cancer as the primary outcome. A total of 180,284 eligible participants from 980 villages were enrolled over 11.8 years of follow-up, and a total of 1,035 cases of incident gastric cancer were documented. Individuals receiving anti-H. pylori therapy showed a modest reduction in gastric cancer incidence in intention-to-treat analyses (hazard ratio 0.86, 95% confidence interval 0.74-0.99), with a stronger effect observed for those having successful H. pylori eradication (hazard ratio 0.81, 95% confidence interval 0.69-0.96) than for those who failed treatment. Moderate adverse effects were reported in 1,345 participants during the 10-day treatment. We observed no severe intolerable adverse events during either treatment or follow-up. The findings suggest the potential for H. pylori mass screening and eradication as a public health policy for gastric cancer prevention.

Importance:Helicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown. Objective:To examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk. Design, Setting, and Participants:This cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu. Exposures:H pylori treatment and nutrition supplementation. Main Outcomes and Measures:Primary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk. Results:Our analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation. Conclusions and Relevance:The findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.

Table S1. Differentially methylated CpGs of non-clustered PCDHs by H. pylori eradication in the whole-genome methylation profiling. Table S2. The association between major characteristics and methylation of four PCDH genes. Table S3. Associations between DNA methylation levels and expression. Table S4. PCR primers and experiment condition of candidate genes. Details for immunohistochemical staining

Background Gastric cancer (GC) develops through a cascade progression of gastric lesions involving multiple genetic alterations. Whether the beneficial effect of Helicobacter pylori (H.pylori) treatment and nutrition supplementation may only apply to potential genetic subgroups remains unknown. We examined genetic variants associated with the progression of gastric lesions and incident GC risk and assessed the effect of primary prevention on GC in individuals with different genetic risks. Methods Our study leveraged two population-based prospective studies in China, including the Shandong Intervention Trial (SIT) and China Kadoorie Biobank (CKB). Based on SIT (discovery set, n=2816), a longitudinal genome-wide association study was conducted to identify genetic variants associated with gastric lesion progression, integrating multiple-time histopathological diagnoses of gastric lesions. Significant genetic variants were examined for GC risk in a randomly sampled validation set (n=50110) of CKB. Independent variants were combined to construct polygenic risk scores (PRSs), further assessed for GC risk in the remaining participants of CKB as a test set (n=50529). The effect of H. pylori treatment and nutrition supplementation was evaluated among SIT attendants with different genetic risks (IDDF2023-ABS-0124 Figure 1. Study design). Results We newly identified 12 genomic loci associated with gastric lesion progression and incident GC risk and derived a PRS prospectively predicting GC risk (HR=1.34, 95%CI:1.27-1.43, per SD increase). Applying the PRS to SIT, a favorable effect of H.pylori treatment on GC was observed among those with high genetic risk (top 25% of PRS, HR=0.47 (0.26-0.87)), but not for the low genetic risk group (HR=0.83 (0.51-1.37), p-interaction=0.03) (IDDF2023-ABS-0124 Figure 2. The effect of H.pylori treatment, vitamin supplementation and garlic supplementation on the risk of incident gastric cancer for individuals with low or high genetic risk in the Shandong intervention trial). For those without H.pylori treatment, vitamin supplementation only benefitted high genetic-risk individuals (IDDF2023-ABS-0124 Figure 3. The effect of vitamin supplementation and garlic supplementation on the risk of incident gastric cancer for individuals with low or high genetic risk who did not accept H.pylori treatment in the Shandong intervention trial). Further functional annotation implied potential biological importance for GC development. Conclusions We found novel genetic variants for GC development, corroborating genetic predisposition underlying GC cascade evolution. H.pylori treatment and vitamin supplementation particularly benefited individuals with the top 25% of PRS, demonstrating that a high genetic risk may be offset by appropriate primary GC prevention. Our results suggest that chemoprevention strategies be tailored to genetic risk for efficient precision GC prevention.

In this study, a panel was established including differential metabolites, genera, and their interactions, which may help to discriminate high-risk subjects for progression from mild lesions to advanced precancerous lesions in short-term and long-term follow-up.

Supplementary Table 2 from Manganese Superoxide Dismutase Polymorphism and Risk of Gastric Lesions, and Its Effects on Chemoprevention in a Chinese Population

Supplementary Table 3 from Manganese Superoxide Dismutase Polymorphism and Risk of Gastric Lesions, and Its Effects on Chemoprevention in a Chinese Population

Figure S1. Representative pictures of immunohistochemical staining for PCDH10 and PCDH17 (20X) PCDH10 and PCDH17 were expressed in the membrane and cytoplasm of epithelial and some stromal cell. (a, b) Representative pictures of immunohistochemical staining for PCDH10 negative and positive expression. (c, d) Representative pictures of immunohistochemical staining for PCDH17 negative and positive expression.

The association of evolutions of Ind DYS/DYS subjects with COX-2 expression changes.

Supplementary Table 1 from Manganese Superoxide Dismutase Polymorphism and Risk of Gastric Lesions, and Its Effects on Chemoprevention in a Chinese Population

Background:Allium vegetable components have antibacterial, antioxidative, and immune modulation properties, thus potentially exhibiting antitumor effects. Despite evidence from case-control studies, prospective studies linking allium vegetables with gastric cancer (GC) have been sparse. Objective: In a prospective study, we examined whether allium vegetable intake would change the risk of GC occurrence and whether the associations would be modified by vitamin supplementation, garlic supplementation, and Helicobacter pylori (H. pylori) treatment. Methods: The study was conducted on the basis of the Shandong Intervention Trial, a randomized, placebo-controlled, factorial-designed trial (1995-2003) in a well-recognized high-risk area for GC in China. Participants were continuously followed up to December 2017 for 22.3 y (1995-2017). A total of 3229 subjects were included, with information on the intake of allium vegetables (garlic vegetables and scallions), collected by structured questionnaires in 1994. The associations of total and individual allium vegetable intake with the risk of GC were examined, respectively. Results: During the follow-up, 144 incident cases of GC were identified. Garlic vegetable intake was associated with a decreased risk of incident GC (P-trend = 0.02; OR: 0.83; 95% CI: 0.70, 0.98, per 1 kg/y increment), whereas scallion intake showed no association (P-trend = 0.80). An inverse association of the risk of GC with total allium vegetable and garlic vegetable intake was particularly stronger among those receiving the placebo for vitamin supplementation or garlic supplementation, indicating potential effect modifications by nutritional supplementation on allium vegetable intake and the risk of developing GC. Similar findings were found for analyses of the combined prevalence of dysplasia or GC. Conclusions: We found a significant reduction in the risk of developing GC with increasing dietary intake of allium vegetables, particularly garlic vegetables. The findings add to the literature on the potential inverse association of garlic vegetable intake with the risk of GC, therefore holding public health implications for dietary recommendations. This trial was registered at clinicaltrials.gov as NCT00339768.

Background and Aim: Methylation alterations may be involved in Helicobacter pylori-associated gastric carcinogenesis. This study aims to explore the potential H.pylori-associated methylation biomarkers in blood leukocyte and gastric mucosa. Methods: Five candidate H.pylori-associated aberrant methylation genes were selected from the previous genome-wide profiling panels and validated in blood leukocyte and gastric mucosa in multi-stages (case-control validation between H.pylori positive and negative subjects and self-control validation before and after anti-H.pylori treatment). Results: GNAS methylation level was decreased in blood leukocyte (62.07% v.s. 46.33%, p<0.001) and gastric mucosa (56.30% v.s. 32.42%, p<0.001) of H.pylori positive subjects compared to negative controls. While, MTERF1 methylation level was increased significantly in blood leukocyte (29.57% v.s. 56.02%, p<0.001) and gastric mucosa (31.10% v.s. 47.50%, p<0.001) of positive subjects compared to controls. After successful H.pylori eradication, the methylation levels were increased from 44.87% to 60.88% (p<0.001) for GNAS and decreased from 46.19% to 34.56% (p<0.001) for MTERF1 in blood leukocyte. Similar increasing and decreasing methylation alterations were also found for the two genes after successful eradication in paired gastric mucosa. In TCGA database, an inverse relationship was found between GNAS methylation and mRNA expression (r=-0.12, p=0.027). The GC cases with higher GNAS expression levels showed significantly worse survival (HR, 2.09, 95%CI, 1.22-3.57, p=0.007) compared to lower expression subjects. Conclusions: GNAS and MTERF1 methylation levels may be affected by H.pylori infection in gastric mucosa and blood leukocyte. GNAS may be involved in advanced stage of GC development, although the possible mechanism still needs further study in precancerous lesions.

In addition to Helicobacter pylori (H.pylori), gastric microbiota may be involved in carcinogenesis process. However, the longitudinal study to assess changes in the gastric microbiota associated with the development of gastric carcinogenesis is still limited. The aim of this study is to explore dynamic microbial alterations in gastric cancer (GC) development based on a 4-year endoscopic follow-up cohort in Linqu County, China. Microbial alterations were investigated by deep sequencing of the microbial 16S ribosomal RNA gene in 179 subjects with various gastric lesions, and validated in paired gastric biopsies prospectively collected before and after lesion progression and in non-progression controls. Significant differences were found in microbial diversity and community structure across various gastric lesions, with 62 candidate differential taxa between at least two lesion groups. Further validations identified Helicobacter, Bacillus, Capnocytophaga and Prevotella to be associated with lesion progression-to-dysplasia (DYS)/GC (all P < 0.05), especially for subjects progressing from intestinal metaplasia (IM) to DYS/GC. The combination of the four genera in a microbial dysbiosis index showed a significant difference after lesion progression-to-DYS/GC compared to controls (P = 0.027). The panel including the four genera identified subjects after progression-to-DYS/GC with an area under the receiver-operating curve (AUC) of 0.941. Predictive significance was found before lesion progression-to-DYS/GC with an AUC = 0.776 and an even better AUC (0.927) for subjects progressing from IM to DYS/GC. Microbiota may play different roles at different stages in gastric carcinogenesis. A panel of bacterial genera associated with gastric lesions may help to assess gastric microbial dysbiosis and show potential predictive values for lesion progression. Our findings provide new clues for the microbial mechanism of H.pylori-associated carcinogenesis.

Background The effectiveness of endoscopic screening on gastric cancer has not been widely investigated in China and the screening interval of repeated screening has not been determined. Methods In a population-based prospective study, we included 375,800 individuals, 14,670 of whom underwent endoscopic screening (2012-2018). We assessed the associations between endoscopic screening and risk of incident gastric cancer and gastric cancer-specific mortality, and examined changes in overall survival and disease-specific survival following screening. The optimal screening interval for repeated endoscopy for early detection of gastric cancer was explored. Results Ever receiving endoscopic screening significantly decreased the risk of invasive gastric cancer (age- and sex-adjusted relative risk [RR] 0.69, 95 % confidence interval [CI] 0.52-0.92) and gastric cancer-specific mortality (RR 0.33, 95 %CI 0.20-0.56), particularly for noncardia gastric cancer. Repeated screening strengthened the beneficial effect on invasive gastric cancer-specific mortality of one-time screening. Among invasive gastric cancers, screening-detected individuals had significantly better overall survival (RR 0.18, 95 %CI 0.13-0.25) and disease-specific survival (RR 0.18, 95 %CI 0.13-0.25) than unscreened individuals, particularly for those receiving repeated endoscopy. For individuals with intestinal metaplasia or low grade intraepithelial neoplasia, repeated endoscopy at an interval of < 2 years, particularly within 1 year, significantly enhanced the detection of early gastric cancer, compared with repeated screening after 2 years ( P-trend = 0.02). Conclusion Endoscopic screening prevented gastric cancer occurrence and death, and improved its prognosis in a population-based study. Repeated endoscopy enhanced the effectiveness. Screening interval should be based on gastric lesion severity.

Objective: To establish the key question list for the development of evidence- based guideline in China according to the content and limitation of current evidence-based guidelines around the world. Methods: First, we introduced the evidence-based guidelines in detail which met the criteria based on World Health Organization guideline development handbook and then formulated the draft list of key questions for the development of evidence-based guidelines. At last, the Delphi method was used to determine the list of key questions in developing evidence-based guidelines of colorectal cancer screening. Results: Totally, 34 questionnaires were collected, with experts from clinical and epidemiological fields. The average experts' authority coefficient was 0.81, indicating a high degree of authority. The concentration of opinions on all items in the questionnaire was relatively high, with the full score ratio greater than 75% and the coefficient of variation less than 0.3. The list of key questions on evidence-based guidelines for colorectal cancer screening has been divided into six parts: epidemiological problems, risk classification, screening age, screening tools, implementation and selection of steering group members, which covers the issues that need to be considered in the development of evidence-based colorectal cancer screening guidelines in China. Conclusion: The key question list for evidence-based guideline development in our study can be applied to the development of evidence-based guidelines for colorectal cancer screening in the future, as well as the development of evidence-based guidelines for other cancer screening in China.

Key Points Question Are lifestyle factors associated with increased risk of gastric cancer (GC), and are they associated with changes in the long-term effects of vitamin and garlic supplementation on GC prevention in high-risk populations in China? Findings In this secondary analysis of a randomized clinical trial with 3365 participants, smoking, but not alcohol intake, was associated with increased risk of GC incidence and mortality; the beneficial effect of garlic supplementation on GC prevention was stronger for individuals who did not drink alcohol. Meaning The findings of this study provide evidence on the association of lifestyle factors with GC in high-risk populations and suggest that mass GC prevention strategies should be tailored to specific population subgroups to maximize potential beneficial effects.

Objective Gastrointestinal microbiota may be involved in Helicobacter pylori-associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from H. pylori infection. Design Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti-H. pylori treatment, relative to 49 H. pylori negative subjects. Results In H. pylori positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in H. pylori positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between Helicobacter and Fusobacterium, Neisseria, Prevotella, Veillonella, Rothia were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased Bifidobacterium after successful H. pylori eradication and more upregulated drug-resistant functional orthologs after failed treatment. Conclusion H. pylori infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful H. pylori eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.