Helicobacter pylori eradication and gastric cancer prevention: Pooled analysis of large-scale cohort studies in Japan

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Although H. pylori eradication is suggested to decrease gastric cancer risk, this has not been fully investigated in general populations. This analysis included 48,530 Japanese men and women aged 40-74 years from four cohort studies. At baseline, the participants provided a self-reported eradication history, and serum anti- H. pylori IgG titers and the atrophic gastritis (AG) severity. We examined the association between eradication history and gastric cancer risk with consideration to H. pylori positivity and AG by Cox proportional hazards regression models. From 2010 to 2018 (average 5.8 years), 649 gastric cancer cases were diagnosed. Compared with those who were negative for both H. pylori and AG as reference, gastric cancer risk was 5.89 times higher (95%CI: 4.41-7.87) in those who were H. pylori positive and/or AG and with no eradication at baseline. Gastric cancer risk among those who underwent eradication before baseline decreased after a temporal increase in risk following eradication (baseline to <1y: HR 1.74, 95%CI 1.18-2.57; 1y to <6y: HR 0.81, 95%CI 0.59-1.11; ≥6y: HR 0.44, 95%CI 0.28-0.68). In a large Japanese general population, H. pylori eradication was associated with long-term reduction in gastric cancer risk. Health sciences/Medical research/Epidemiology Health sciences/Oncology/Cancer/Cancer prevention Health sciences/Oncology/Cancer/Cancer screening Health sciences/Oncology/Cancer/Gastrointestinal cancer/Gastric cancer Health sciences/Risk factors Gastric cancer Helicobacter pylori atrophic gastritis eradication prospective cohort study Japan Figures Figure 1 1. Introduction Gastric cancer affected 0.97 million people worldwide in 2022, making it the fifth-most common cancer and cause of cancer death globally that year 1 . In Japan, gastric cancer was the leading cause of death by cancer site until 1998, and ranked third in 2022 2 . Helicobacter pylori (H. pylori) infection is listed as a Group 1 Carcinogen by the International Agency for Research on Cancer (IARC) and is the most important factor in the development of gastric cancer 3, 4 . Gastric cancer develops in 5% of H. pylori -positive individuals over 10 years, according to estimates of the Japanese population 5 . The effect of infection varies according to the infecting H. pylori strain, and is not uniform worldwide 6, 7 . A meta-analysis which included randomized control trials confirmed that H. pylori eradication is associated with a reduced incidence of gastric cancer 8 . However, whether eradication also prevents gastric cancer in the general population has not been determined 9 . Here, we conducted a pooled analysis of ongoing population-based cohort studies in Japan to determine the risk of developing gastric cancer after H. pylori eradication in a general population setting. 2. Results The present study included 48,530 participants for analysis (average age at baseline: 60.3 years old), among whom 649 gastric cancers were newly diagnosed. Participant baseline characteristics are shown in Table 1 . A total of 11.7% of participants had an eradication history at baseline survey. Men had a higher proportion of eradication treatment history than women (14.4% vs 9.6%). Selected characteristics of the study participants according to H. pylori infection status are shown in Table S1. Table 2 shows the results of gastric cancer risk by length of time between eradication and baseline. Among those with no history of eradication, participants who were H. pylori -positive and/or AG-positive had higher risk of gastric cancer (HR 5.89, 95%CI: 4.41-7.87) compared with those who were H. pylori -negative and AG-negative. Further, risk was increased in those who were H. pylo ri-positive and AG-negative (HR 3.62, 95% CI: 2.60-5.03), and further increased in those who were AG-positive (HR 7.67, 95% CI: 5.69-10.34 for those who were both H. pylori- positive and AG-positive; and HR 8.79, 95%CI: 6.04-12.80 for those who were H. pylo ri-negative and AG-positive). When analysis was restricted to participants with H. pylori infection ( H. pylori -positive and/or AG-positive), compared with those with no history of eradication as reference, risk was increased for those who had undergone eradication less than 1 year before baseline (HR 1.74, 95%CI: 1.18-2.57) but decreased for those who had undergone eradication 1-6 years and 6 or more years before baseline (HR 0.81, 95%CI: 0.59-1.11; HR 0.44, 95%CI: 0.28-0.68, respectively). Table 3 shows gastric cancer risk by period after H. pylori eradication based on the 5-year follow-up survey. Among participants followed from baseline to the 5-year follow-up survey, only those with a positive H. pylori infection status ( H. pylori -positive and/or AG-positive) and who self-reported an eradication history at both the baseline and 5-year follow-up surveys were included. Compared to those with no eradication, gastric cancer risk declined after eradication between baseline and the 5-year follow-up survey (HR 0.86, 95％CI: 0.57-1.28 for <1 year at the 5-year follow-up survey; and HR 0.81, 95％CI: 0.63-1.04 for 1-6 years at the 5-year follow-up survey). The complete case analysis – performed as a sensitivity analysis – and the analysis by age group showed no significant differences from the original analysis (data not shown). 3. Discussion To our knowledge, this is the first report to examine the association between H. pylori eradication and gastric cancer risk in a large-scale prospective cohort study of a general Japanese population. We observed that the risk of gastric cancer among those who received eradication before baseline decreased with increasing time after a temporal increase in risk immediately following eradication, which suggests that gastric cancer risk is decreased in the long term by H. pylori eradication for those at high risk of gastric cancer in a general population setting. Eradication was shown to be more likely to reduce gastric cancer risk if performed in the early phase of infection both in an experiment 17 and in an epidemiological study for individuals with few symptoms or mild gastric atrophy 18 . Risk showed a decreasing trend among participants who first underwent eradication between baseline and the 5-year follow-up survey following a temporal increase in risk just after eradication. The accuracy of risk evaluation after eradication is difficult to determine because a diagnosis of early gastric cancer during this period necessarily includes an increased number of endoscopies before and after eradication, as well as the results of oversight of early gastric cancer during endoscopy performed prior to eradication. One mechanism underlying the association between H. pylori eradication and gastric cancer development may be deoxyribonucleic acid (DNA) methylation induced by chronic H. pylori infection-associated inflammation 19, 20 . Cytotoxin-associated Gene A (CagA) is a well-known toxic agent of H. pylori which plays an important role in carcinogenesis 6 . Injected into gastric cells, CagA binds to breast cancer susceptibility gene 1 (BRCA1) and promotes the accumulation of genetic mutations 21 . H. pylori eradication decreases the effects of DNA methylation abnormalities and CagA, suggesting that eradication may have a preventive effect on carcinogenesis. If these abnormalities occur not only in gastric epithelial cells but also in stem cells 22 , the abnormalities may remain after eradication 23 . This might in turn explain why carcinogenic risk does not recover to levels seen in healthy individuals after eradication. The main strengths of this investigation are its large, well-characterized Japanese cohort and collection of information prior to a diagnosis of gastric cancer, eliminating recall bias. Nevertheless, some methodological limitations also warrant mention. First, participants’ self-reported H. pylori eradication history was not confirmed by treatments they had received, and may be subject to misclassification due to misidentification, with accidental eradication being a possible cause 23 . We assume that the results of medical records survey 13 and medical claims data 14 have sufficient validity. Second, we did not consider the results of treatment assessment and secondary eradication due to the high first-time eradication success rate, which may cause the effect of eradication to be underestimated. In addition, some gastric cancers were diagnosed during the follow-up period among those classified as both H. pylori - and AG-negative; these might be gastric cancers unrelated to H. pylori or attributable to misclassification by accidental eradication from other treatments or forgotten eradication reports. Participants who had undergone eradication before baseline may have had advanced symptoms, such as peptic ulcers. This is because eradication was covered by health insurance for these individuals. Insurance coverage was subsequently extended to include “ H. pylori -gastritis” after February 2013, which resulted in a marked nationwide increase in the number of patients undergoing eradication, from approximately 650,000 per year in 2001-2012 to 1.38 million per year in 2013 24 . The effectiveness of eradication in the short follow-up period may have been influenced by differences in the timing of eradication, namely before or after health insurance coverage, and in whether the participant was symptomatic or not. In addition, a simulation study estimated that the 2013 coverage of eradication for H. pylori -gastritis in Japan will result in a decrease in prevalence of H. pylori infection by 2050 to 5%, versus 22% if coverage had not been provided 24 . In the present study, because coverage eradication of H. pylori -gastritis by health insurance was initiated during the study period, participant background may have differed before and after insurance coverage, although were unable to investigate this in detail. Given these changes in medical conditions, risk reduction by early eradication and early detection using appropriate long-term endoscopic examination should be considered essential components of any gastric cancer prevention strategy. In conclusion, we found that H. pylori eradication was associated with a decrease in long-term gastric cancer risk, albeit that there was a temporal increase in risk during the post-eradication observation period in a large Japanese general population. These findings may aid risk stratification in the strategic prevention of gastric cancer and future promotion of prevention. 4. Materials and Methods Study population The study was conducted using prospective cohort study data of residents aged 40-74 in four areas: Yamagata, Saku, Yokote, and Chikusei. The Yamagata area initiated the present study in 2009 under the protocol of the Yamagata Study. Blood samples were collected with consent at the time of health examinations, and questionnaires were conducted at baseline and at the 5-year follow-up survey. Medical information derived from health insurance, cancer diagnosis by cancer registries, and deaths were captured during follow-up. The Saku, Yokote, and Chikusei areas initiated the study under the protocol of The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT Study), which was initiated in 2011, targeting residents in each area. Questionnaire surveys and blood sampling were conducted at baseline and at the time of the 5-year follow-up survey. Participants were followed for vital status, cause of death and residential relocation by the residential registry or death certificates, with consent. Both the Yamagata Study and JPHC-NEXT Study were designed to identify lifestyle, environmental and genetic factors in the development of lifestyle-related diseases. The two large cohort studies are described in detail elsewhere 10, 11 . We initially included 49,140 residents aged 40-74 years in the four areas who participated in the baseline survey and had blood sampling. After those with a history of gastric cancer as determined by self-report or the cancer registries before baseline were excluded (n=610), 48,530 participants were regarded as eligible for analysis. Among these, 32,196 participants answered the questionnaire of the 5-year follow-up survey. After excluding those who were treated for H. pylori eradication prior to baseline survey (n=3,658), were both H. pylori antibody- and AG-negative (n=13,240), or were treated for eradication at an unknown time (n=2,214), participants who were H. pylori antibody-positive and/or AG-positive (n=13,084) were included in further analysis. The study flow is shown in Figure 1 . Assessment of H. pylori infection status This study used serum samples obtained during health examinations or study-specific blood sampling opportunities. Serum anti- H. pylori IgG antibodies were measured using enzyme-linked immunosorbent assay (ELISA; E-Plate Eiken or E-Plate II Eiken; Eiken Chemical Co., Ltd., Japan). We defined values of 10 U/mL or higher as positive, which was the standard cut-off point at the time the study was initiated. As a marker of atrophic gastritis (AG), serum levels of pepsinogen (PG) I and II were measured by latex agglutination (LZ test “Eiken” Pepsinogen I, II; Eiken Kagaku). AG was determined to be negative at PG I >70 ng/mL or PG I/II >3.0, or positive at PG I ≤ 70 ng/mL and PG I/II ratio ≤ 3.0 12 . Participants were then categorized into five groups by H. pylori infection status according to the results forserumanti- H. pylori IgG antibodies and AG, namely H. pylori -negative and AG-negative; H. pylori -positive and AG-negative; H. pylori -positive and AG-positive; H. pylori -negative and AG-positive; and self-reported history of H. pylori eradication before baseline survey. Assessment for H. pylori eradication history In the Yamagata Study, we inquired about participants’ H. pylori eradication status using the following questions: (1) “Have you ever been tested for H. pylori ?” (Yes/No) (2) “Have you received H. pylori eradication?” (Yes/No), (3) “At what age did you receive H. pylori eradication?” In the JPHC-NEXT, we asked “Have you ever received H. pylori eradication?” (No history/Received). Participants who reported previous eradication were additionally asked about the length of time between eradication and baseline (<1 year, 1 year to <6 years, ≥ 6 years). We matched eradication age in the Yamagata study participants to the JPHC-NEXT response categories. Those who underwent eradication after gastric cancer diagnosis were reclassified as no-eradication. The validity of a self-reported H. pylori eradication history in this study has been confirmed elsewhere 13, 14 . Follow-up and identification of gastric cancer Participants were followed from the date of study entry at baseline until gastric cancer diagnosis, movement out of the study area, death, or the end of follow-up (December 31, 2018), whichever occurred first. Data on survival, moving out of the study area and death were identified from residence records. Information on the study outcome – gastric cancer (Code C16.0-16.9) diagnosed during the study period – was obtained from major local hospitals as well as regional (until 2015) and national cancer registries (from 2016) in accordance with the Cancer Registry Promotion Act, and prepared for analysis in this study and processed independently. Cases were coded using the International Classification of Diseases for Oncology (ICD-O), Third Edition 15 . Statistical analysis Hazard ratios (HRs) and 95% confidence intervals (CIs) for developing gastric cancer by category of years since eradication were determined using Cox proportional hazards models, controlling for the following potential confounders: sex, age at baseline (5-year categories), smoking status (never, current, former), and alcohol consumption (pure ethanol per week; never or rarely, <150 g/week, 150 to 300 g/week, 300 g/week or more). These variables were selected based on associations identified in a previous study 16 . Missing values were also incorporated as missing indicator variables in the analysis. Heterogeneity across the study areas was accounted for by including the study area as a strata variable in the Cox model. We also estimated HRs stratified by H. pylori infection status. Some participants who completed the 5-year follow-up survey underwent eradication between baseline and the 5-year follow-up survey. Additional sensitivity analyses were conducted based on complete-case analysis, which excluded all cases with missing values, and in participants with inconsistent responses between the baseline and 5-year follow-up survey. Testing of the proportional hazards’ assumption using Schoenfeld and scaled Schoenfeld residuals found no violation of proportionality. All p -values reported were two-sided, with p < 0.05 set as the statistical significance level. All statistical analyses were performed using Stata 17 (Stata Corp). Abbreviations CI, confidence interval; HR, hazard ratio; JPHC-NEXT, The Japan Public Health Center-based Prospective Study for Next Generation; PHC, public health center Declarations Ethics statement The study was conducted conforming to the Declaration of Helsinki and the Ethical Guidelines for Medical and Biological Research Involving Human Subjects, and was initiated in each cohort by obtaining written informed consent from all participants at the time of study enrollment. The individual study protocols were approved by the Institutional Review Board of Yamagata University Faculty of Medicine (#2019-175) and the National Cancer Center Japan (2011-186), and the pooled analysis protocol was approved by Yamagata University Faculty of Medicine (#2019-175) and the National Cancer Center Japan (2017-243). Data availability statement JPHC-NEXT and Yamagata studies are not publicly available because currently open only to researchers of Japanese nationality who meet the research requirements and are available from the corresponding author upon reasonable request. Investigators planning to access both study data must receive approval from relevant committees. For JPHC-NEXT, approval is required from both the JPHC-NEXT Steering Committee (SC) and the Institutional Review Board (IRB) of the National Cancer Center (NCC). Researchers must submit a Project Protocol (including research question, objectives, background, design, and analysis plan) for review by the JPHC-NEXT SC. Similarly, the Yamagata Study requires approval from the Cohort Steering Committee and the Institute's Steering Committee at the Yamagata University Well-Being Institute, with additional approval from the School of Medicine Ethics Review Committee for post-approval data. Requests can be made by contacting the JPHC SC directly ( [email protected] ) or contacting the Cohort Management Promotion Department ( [email protected] ) for information on applying for the Yamagata Study. Author Contribution Author’s contributions: MI responsible for the concept and design of the study and supervised the project. A.O., S.T., N.S., A.G., S.T., I.M., K.Y., Y.S., Y.A. and T.Y. contributed to data acquisition. A.O., N.S. and M.I. contributed to the analysis and interpretation of data. A.O. and M.I. drafted the manuscript. S.T., N.S., A.G., S.T., I.M., K.Y., Y.S., Y.A., T.K., Y.U., E.S., T.Y., M.I. and M.I. critically revised the manuscript for important intellectual content. All authors reviewed the manuscripts and contributed to the revision. Acknowledgement We appreciate all participants and staff members in each study area for their efforts in conducting the baseline and follow-up surveys. Funding information This work was funded by the National Cancer Center Research and Development Fund [23-A-31(toku), 26-A-2, 29-A-4] (since 2011), Research and Development by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (2011–2013), and by Practical Research for Innovative Cancer Control, Japan Cancer Research Project, Japan Agency for Medical Research and Development (AMED) (17ck0106277h0001,18ck0106277h0002,19ck0106277h0003,20ck0106561h0001,20ck0106561h0001RR,21ck0106561h0002,21ck0106561h0002RR,22ck0106561h0003, 22ck0106561h0003RR), and in part by the Japan Society for the Promotion of Science KAKENHI Grant Number JP20K08350 for the Yamaga Cohort. Author’s contributions MI responsible for the concept and design of the study and supervised the project. AO, ST, NS, AG, ST, IM, KY, YS, YA and TY contributed to data acquisition. AO, NS and MI contributed to the analysis and interpretation of data. AO and MI drafted the manuscript. ST, NS, AG, ST, IM, KY, YS, YA, TK, YU, ES, TY, MI and MI critically revised the manuscript for important intellectual content. All authors reviewed the manuscripts and contributed to the revision. Disclosure of conflicts of interest The authors declare no conflicts of interest. References Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-263. Ferlay J EM, Lam F, Laversanne M, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F. Global Cancer Observatory: Cancer Today (version 1.1). Lyon, France: International Agency for Research on Cancer., 2024,accessed[02 Aug 2024]. Cancer WIAfRo. IARC monographs on the identification of carcinogenic hazards to humans, 2022. Inoue M. Changing epidemiology of Helicobacter pylori in Japan. Gastric Cancer 2017;20:3-7. Charvat H, Sasazuki S, Inoue M, et al. 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Impact of health insurance coverage for Helicobacter pylori gastritis on the trends in eradication therapy in Japan: retrospective observational study and simulation study based on real-world data. BMJ Open 2017;7:e015855. Tables Tables 1 to 3 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files TableS1.docx Supplementary Appendix: Table S1 Tables.docx Cite Share Download PDF Status: Published Journal Publication published 01 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 30 Sep, 2024 Reviews received at journal 19 Sep, 2024 Reviews received at journal 13 Sep, 2024 Reviewers agreed at journal 13 Sep, 2024 Reviewers agreed at journal 13 Sep, 2024 Reviewers invited by journal 13 Sep, 2024 Editor assigned by journal 13 Sep, 2024 Editor invited by journal 10 Sep, 2024 Submission checks completed at journal 09 Sep, 2024 First submitted to journal 05 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5036019","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":360595620,"identity":"d137bd37-a477-45a1-92ff-ebbd81d23962","order_by":0,"name":"Ayami Ono","email":"","orcid":"","institution":"National Cancer Center Institute for Cancer Control","correspondingAuthor":false,"prefix":"","firstName":"Ayami","middleName":"","lastName":"Ono","suffix":""},{"id":360595621,"identity":"fc4da2e1-255d-46ad-95f2-29c84c3dd2e7","order_by":1,"name":"Shiori Tanaka","email":"","orcid":"","institution":"National Cancer Center Institute for Cancer 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Control","correspondingAuthor":false,"prefix":"","firstName":"Motoki","middleName":"","lastName":"Iwasaki","suffix":""},{"id":360595634,"identity":"2f302b12-67e0-4fe1-ae32-f9488eb1c8c8","order_by":14,"name":"Manami Inoue","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYJCCAyCCH8ZjbCBWiyRMJVFawMDgALEqdWd3Jx4uqDgsZ3y7+eEHhl82DMyzCVhjdufshsMzzhw2NrtzzFiCsS+NgXEOAfvMbuRuOMzbdjhx240cNgbGnsMMjDMSiNNSv3kGqVoSDCSAWhh+EKuF50y64YwbacYSiQ1pPMT4ZfNnngpref4ZyQ8/fPhjI2dIKMRQQWIbA4/hDFJ0MDD8YWCQlyBNyygYBaNgFAx/AACYAUiFBh8nugAAAABJRU5ErkJggg==","orcid":"","institution":"National Cancer Center Institute for Cancer Control","correspondingAuthor":true,"prefix":"","firstName":"Manami","middleName":"","lastName":"Inoue","suffix":""}],"badges":[],"createdAt":"2024-09-05 07:21:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5036019/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5036019/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-00713-z","type":"published","date":"2025-07-01T15:58:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69836033,"identity":"4f5a53d1-8d5b-463a-9865-818af5fe8fa4","added_by":"auto","created_at":"2024-11-25 16:15:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1171348,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5036019/v1/c37da297cda6c13aaa3ce1bc.jpg"},{"id":86180259,"identity":"32e9ee13-6377-4d1c-9a57-2f57e4096467","added_by":"auto","created_at":"2025-07-07 16:21:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1736679,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5036019/v1/76202c53-0f0d-49fb-9ba3-c6b595bb0c92.pdf"},{"id":69836032,"identity":"e82e7473-cffd-4371-b84c-b722e5e933f3","added_by":"auto","created_at":"2024-11-25 16:15:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34924,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Appendix: Table S1\u003c/p\u003e","description":"","filename":"TableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5036019/v1/3940b884814d347e45097d54.docx"},{"id":69836031,"identity":"d87a2523-d7fb-4dd7-bfbb-3d9201110e66","added_by":"auto","created_at":"2024-11-25 16:15:51","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":41095,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-5036019/v1/6f24a0088f01da24a98ca324.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Helicobacter pylori eradication and gastric cancer prevention: Pooled analysis of large-scale cohort studies in Japan","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eGastric cancer affected 0.97 million people worldwide in 2022, making it the fifth-most common cancer and cause of cancer death globally that year\u003csup\u003e1\u003c/sup\u003e. In Japan, gastric cancer was the leading cause of death by cancer site until 1998, and ranked third in 2022 \u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHelicobacter pylori (H. pylori)\u003c/em\u003e infection is listed as a Group 1 Carcinogen by the International Agency for Research on Cancer (IARC) and is the most important factor in the development of gastric cancer \u003csup\u003e3, 4\u003c/sup\u003e. Gastric cancer develops in 5% of\u003cem\u003e\u0026nbsp;H. pylori\u003c/em\u003e-positive individuals over 10 years, according to estimates of the Japanese population \u003csup\u003e5\u003c/sup\u003e. The effect of infection varies according to the infecting \u003cem\u003eH. pylori\u003c/em\u003e strain, and is not uniform worldwide\u003csup\u003e6, 7\u003c/sup\u003e. A meta-analysis which included randomized control trials confirmed that \u003cem\u003eH. pylori\u003c/em\u003e eradication is associated with a reduced incidence of gastric cancer \u003csup\u003e8\u003c/sup\u003e. However, whether eradication also prevents gastric cancer in the general population has not been determined \u003csup\u003e9\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHere, we conducted a pooled analysis of ongoing population-based cohort studies in Japan to determine the risk of developing gastric cancer after\u003cem\u003e\u0026nbsp;H. pylori\u003c/em\u003e eradication in a general population setting.\u003c/p\u003e"},{"header":"2. Results ","content":"\u003cp\u003eThe present study included 48,530 participants for analysis (average age at baseline: 60.3 years old), among whom 649 gastric cancers were newly diagnosed. Participant baseline characteristics are shown in \u003cstrong\u003eTable 1\u003c/strong\u003e. A total of 11.7% of participants had an eradication history at baseline survey. Men had a higher proportion of eradication treatment history than women (14.4% vs 9.6%). Selected characteristics of the study participants according to \u003cem\u003eH. pylori\u003c/em\u003e infection status are shown in \u003cstrong\u003eTable S1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003eshows the results of gastric cancer risk by length of time between eradication and baseline. Among those with no history of eradication, participants who were \u003cem\u003eH. pylori\u003c/em\u003e-positive and/or AG-positive had higher risk of gastric cancer (HR 5.89, 95%CI: 4.41-7.87) compared with those who were \u003cem\u003eH. pylori\u003c/em\u003e-negative and AG-negative. Further, risk was increased in those who were\u003cem\u003e\u0026nbsp;H. pylo\u003c/em\u003eri-positive and AG-negative (HR 3.62, 95% CI: 2.60-5.03), and further increased in those who were AG-positive (HR 7.67, 95% CI: 5.69-10.34 for those who were\u003cem\u003e\u0026nbsp;\u003c/em\u003eboth\u0026nbsp;\u003cem\u003eH. pylori-\u003c/em\u003epositive and AG-positive; and HR 8.79, 95%CI: 6.04-12.80 for those who were\u0026nbsp;\u003cem\u003eH. pylo\u003c/em\u003eri-negative and AG-positive).\u0026nbsp;When analysis was restricted to participants with \u003cem\u003eH. pylori\u0026nbsp;\u003c/em\u003einfection (\u003cem\u003eH. pylori\u003c/em\u003e-positive and/or AG-positive), compared with those with no history of eradication as reference, risk was increased for those who had undergone eradication\u0026nbsp;less than 1 year before baseline (HR 1.74, 95%CI: 1.18-2.57) but decreased for those who had undergone eradication 1-6 years and 6 or more years before baseline (HR 0.81, 95%CI: 0.59-1.11; HR 0.44, 95%CI: 0.28-0.68, respectively).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e shows gastric cancer risk by period after \u003cem\u003eH. pylori\u0026nbsp;\u003c/em\u003eeradication based on the 5-year follow-up survey. Among participants followed from baseline to the 5-year follow-up survey, only those with a positive \u003cem\u003eH. pylori\u003c/em\u003e infection status (\u003cem\u003eH. pylori\u003c/em\u003e-positive and/or AG-positive) and who self-reported an eradication history at both the baseline and 5-year follow-up surveys were included. Compared to those with no eradication, gastric cancer risk declined after eradication between baseline and the 5-year follow-up survey (HR 0.86, 95％CI:\u0026nbsp;0.57-1.28 for \u0026lt;1 year at the 5-year follow-up survey; and HR 0.81, 95％CI:\u0026nbsp;0.63-1.04 for 1-6 years at the 5-year follow-up survey).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe complete case analysis \u0026ndash; performed as a sensitivity analysis \u0026ndash; and the analysis by age group showed no significant differences from the original analysis (data not shown).\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eTo our knowledge, this is the first report to examine the association between \u003cem\u003eH. pylori\u003c/em\u003e eradication and gastric cancer risk in a large-scale prospective cohort study of a general Japanese population. We observed that the risk of gastric cancer among those who received eradication before baseline decreased with increasing time after a temporal increase in risk\u0026nbsp;immediately following eradication, which suggests that gastric cancer risk is decreased in the long term by \u003cem\u003eH. pylori\u003c/em\u003e eradication for those at high risk of gastric cancer in a general population setting.\u003c/p\u003e\n\u003cp\u003eEradication was shown to be more likely to reduce gastric cancer risk if performed in the early phase of infection both in an experiment \u003csup\u003e17\u003c/sup\u003e and in an epidemiological study for individuals with few symptoms or mild gastric atrophy\u0026nbsp;\u003csup\u003e18\u003c/sup\u003e. Risk showed a decreasing trend among participants who first underwent eradication between baseline and the 5-year follow-up survey following a temporal increase in risk just after eradication. The accuracy of risk evaluation after eradication is difficult to determine because a diagnosis of early gastric cancer during this period necessarily includes an increased number of endoscopies before and after eradication, as well as the results of oversight of early gastric cancer during endoscopy performed prior to eradication.\u003c/p\u003e\n\u003cp\u003eOne mechanism underlying the association between \u003cem\u003eH. pylori\u003c/em\u003e eradication and gastric cancer development may be deoxyribonucleic acid (DNA) methylation induced by chronic \u003cem\u003eH. pylori\u003c/em\u003e infection-associated inflammation\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003csup\u003e19, 20\u003c/sup\u003e. Cytotoxin-associated Gene A (CagA) is a well-known toxic agent of \u003cem\u003eH. pylori\u003c/em\u003e which plays an important role in carcinogenesis\u0026nbsp;\u003csup\u003e6\u003c/sup\u003e. Injected into gastric cells, CagA binds to breast cancer susceptibility gene 1 (BRCA1) and promotes the accumulation of genetic mutations\u0026nbsp;\u003csup\u003e21\u003c/sup\u003e. \u003cem\u003eH. pylori\u0026nbsp;\u003c/em\u003eeradication decreases the effects of DNA methylation abnormalities and CagA, suggesting that eradication may have a preventive effect on carcinogenesis. If these abnormalities occur not only in gastric epithelial cells but also in stem cells \u003csup\u003e22\u003c/sup\u003e, the abnormalities may remain after eradication \u003csup\u003e23\u003c/sup\u003e. This might in turn explain why carcinogenic risk does not recover to levels seen in healthy individuals after eradication.\u003c/p\u003e\n\u003cp\u003eThe main strengths of this investigation are its large, well-characterized Japanese cohort and collection of information prior to a diagnosis of gastric cancer, eliminating recall bias. Nevertheless, some methodological limitations also warrant mention. First, participants\u0026rsquo; self-reported \u003cem\u003eH. pylori\u003c/em\u003e eradication history was not confirmed by treatments they had received, and may be subject to misclassification due to misidentification, with accidental eradication being a possible cause \u003csup\u003e23\u003c/sup\u003e. We assume that the results of medical records survey \u003csup\u003e13\u003c/sup\u003e and medical claims data \u003csup\u003e14\u003c/sup\u003e have sufficient validity. Second, we did not consider the results of treatment assessment and secondary eradication due to the high first-time eradication success rate, which may cause the effect of eradication to be underestimated. In addition, some gastric cancers were diagnosed during the follow-up period among those classified as both \u003cem\u003eH. pylori\u003c/em\u003e- and AG-negative; these might be gastric cancers unrelated to \u003cem\u003eH. pylori\u003c/em\u003e or attributable to misclassification by accidental eradication from other treatments or forgotten eradication reports.\u003c/p\u003e\n\u003cp\u003eParticipants who had undergone eradication before baseline may have had advanced symptoms, such as peptic ulcers. This is because eradication was covered by health insurance for these individuals. Insurance coverage was subsequently extended to include \u0026ldquo;\u003cem\u003eH. pylori\u003c/em\u003e-gastritis\u0026rdquo; after February 2013, which resulted in a marked nationwide increase in the number of patients undergoing eradication, from approximately 650,000 per year in 2001-2012 to 1.38 million per year in 2013 \u003csup\u003e24\u003c/sup\u003e. The effectiveness of eradication in the short follow-up period may have been influenced by differences in the timing of eradication, namely before or after health insurance coverage, and in whether the participant was symptomatic or not. In addition, a simulation study estimated that the 2013 coverage of eradication for \u003cem\u003eH. pylori\u003c/em\u003e-gastritis in Japan will result in a decrease in prevalence of \u003cem\u003eH. pylori\u003c/em\u003e infection by\u0026nbsp;2050 to 5%, versus 22% if coverage had not been provided\u0026nbsp;\u003csup\u003e24\u003c/sup\u003e. In the present study, because coverage eradication of \u003cem\u003eH. pylori\u003c/em\u003e-gastritis by health insurance was initiated during the study period, participant background may have differed before and after insurance coverage, although were unable to investigate this in detail. Given these changes in medical conditions, risk reduction by early eradication and early detection using appropriate long-term endoscopic examination should be considered essential components of any gastric cancer prevention strategy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, we found that \u003cem\u003eH. pylori\u003c/em\u003e eradication was associated with a decrease in long-term gastric cancer risk, albeit that there was a temporal increase in risk during the post-eradication observation period in a large Japanese general population. These findings may aid risk stratification in the strategic prevention of gastric cancer and future promotion of prevention.\u003c/p\u003e"},{"header":"4. Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted using prospective cohort study data of residents aged 40-74 in four areas: Yamagata, Saku, Yokote, and Chikusei. The Yamagata area initiated the present study in 2009 under the protocol of the Yamagata Study.\u0026nbsp;Blood samples were collected with consent at the time of health examinations, and questionnaires were conducted at baseline and at the 5-year follow-up survey. Medical information derived from health insurance, cancer diagnosis by cancer registries, and deaths were captured during follow-up.\u0026nbsp;The Saku, Yokote, and Chikusei areas initiated the study under the protocol of The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT Study), which was initiated in 2011, targeting residents in each area. Questionnaire surveys and blood sampling were conducted at baseline and at the time of the 5-year follow-up survey. Participants were followed for vital status, cause of death and residential relocation by the residential registry or death certificates, with consent. Both the Yamagata Study and JPHC-NEXT Study were designed to identify lifestyle, environmental and genetic factors in the development of lifestyle-related diseases. The two large cohort studies are described in detail elsewhere\u0026nbsp;\u003csup\u003e10, 11\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe initially included 49,140 residents aged 40-74 years in the four areas who participated in the baseline survey and had blood sampling. After those with a history of gastric cancer as determined by self-report or the cancer registries before baseline were excluded (n=610), 48,530 participants were regarded as eligible for analysis.\u003c/p\u003e\n\u003cp\u003eAmong these, 32,196 participants answered the questionnaire of the 5-year follow-up survey. After excluding those who were treated for \u003cem\u003eH. pylori\u0026nbsp;\u003c/em\u003eeradication\u0026nbsp;prior to baseline survey (n=3,658), were both \u003cem\u003eH. pylori\u003c/em\u003e antibody- and AG-negative (n=13,240), or were treated for eradication at an unknown time (n=2,214), participants who were \u003cem\u003eH. pylori\u003c/em\u003e antibody-positive and/or AG-positive (n=13,084) were included in further analysis.\u003c/p\u003e\n\u003cp\u003eThe study flow is shown in \u003cstrong\u003eFigure 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment of \u003cem\u003eH. pylori\u0026nbsp;\u003c/em\u003einfection status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study used serum samples obtained during health examinations or study-specific blood sampling opportunities. Serum anti-\u003cem\u003eH. pylori\u003c/em\u003e IgG antibodies were measured using enzyme-linked immunosorbent assay (ELISA; E-Plate Eiken or E-Plate II Eiken; Eiken Chemical Co., Ltd., Japan). We defined values of 10 U/mL or higher as positive, which was the standard cut-off point at the time the study was initiated. As a marker of atrophic gastritis (AG), serum levels of pepsinogen (PG) I and II were measured by latex agglutination (LZ test “Eiken” Pepsinogen I, II; Eiken Kagaku). AG was determined to be negative at PG I \u0026gt;70 ng/mL or PG I/II \u0026gt;3.0, or positive at PG I ≤ 70 ng/mL and PG I/II ratio ≤ 3.0 \u003csup\u003e12\u003c/sup\u003e. Participants were then categorized into five groups by \u003cem\u003eH. pylori\u0026nbsp;\u003c/em\u003einfection status according to the results forserumanti-\u003cem\u003eH. pylori IgG\u0026nbsp;\u003c/em\u003eantibodies and AG, namely \u003cem\u003eH. pylori\u003c/em\u003e-negative and AG-negative; \u003cem\u003eH. pylori\u003c/em\u003e-positive and AG-negative; \u003cem\u003eH. pylori\u003c/em\u003e-positive and AG-positive; \u003cem\u003eH. pylori\u003c/em\u003e-negative and AG-positive; and self-reported history of \u003cem\u003eH. pylori\u003c/em\u003e eradication before baseline survey.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment for \u003cem\u003eH. pylori\u003c/em\u003e eradication history\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the Yamagata Study, we inquired about participants’ \u003cem\u003eH. pylori\u0026nbsp;\u003c/em\u003eeradication status using the following questions: (1) “Have you ever been tested for \u003cem\u003eH. pylori\u003c/em\u003e?” (Yes/No) (2) “Have you received \u003cem\u003eH. pylori\u003c/em\u003e eradication?” (Yes/No), (3) “At what age did you receive \u003cem\u003eH. pylori\u003c/em\u003e eradication?” In the JPHC-NEXT, we asked “Have you ever received \u003cem\u003eH. pylori\u003c/em\u003e eradication?” (No history/Received). Participants who reported previous eradication were additionally asked about the length of time between eradication and baseline (\u0026lt;1 year, 1 year to \u0026lt;6 years, ≥ 6 years). We matched eradication age in the Yamagata study participants to the JPHC-NEXT response categories. Those who underwent eradication after gastric cancer diagnosis were reclassified as no-eradication. The validity of a self-reported \u003cem\u003eH. pylori\u003c/em\u003e eradication history in this study has been confirmed elsewhere \u003csup\u003e13, 14\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up and identification of gastric cancer\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants were followed from the date of study entry at baseline until gastric cancer diagnosis, movement out of the study area, death, or the end of follow-up (December 31, 2018), whichever occurred first. Data on survival, moving out of the study area and death were identified from residence records. Information on the study outcome – gastric cancer (Code C16.0-16.9) diagnosed during the study period – was obtained from major local hospitals as well as regional (until 2015) and national cancer registries (from 2016) in accordance with the Cancer Registry Promotion Act, and prepared for analysis in this study and processed independently. Cases were coded using the International Classification of Diseases for Oncology (ICD-O), Third Edition \u003csup\u003e15\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHazard ratios (HRs) and 95% confidence intervals (CIs) for developing gastric cancer by category of years since eradication were determined using Cox proportional hazards models, controlling for the following potential confounders: sex, age at baseline (5-year categories), smoking status (never, current, former), and alcohol consumption (pure ethanol per week; never or rarely, \u0026lt;150 g/week,\u0026nbsp;150 to 300 g/week, 300 g/week or more). These variables were selected based on associations identified in a previous study \u003csup\u003e16\u003c/sup\u003e. Missing values were also incorporated as missing indicator variables in the analysis. Heterogeneity across the study areas was accounted for by including the study area as a strata variable in the Cox model.\u003c/p\u003e\n\u003cp\u003eWe also estimated HRs stratified by \u003cem\u003eH. pylori\u003c/em\u003e infection status. Some participants\u0026nbsp;who completed the 5-year follow-up survey underwent eradication between baseline and the 5-year follow-up survey. Additional sensitivity analyses were conducted based on complete-case analysis, which excluded all cases with missing values, and in participants with inconsistent responses between the baseline and 5-year follow-up survey. Testing of the proportional hazards’ assumption using Schoenfeld and scaled Schoenfeld residuals found no violation of proportionality. All \u003cem\u003ep\u003c/em\u003e-values reported were two-sided, with \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05 set as the statistical significance level. All statistical analyses were performed using Stata 17 (Stata Corp).\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI, confidence interval; HR, hazard ratio; JPHC-NEXT, The Japan Public Health Center-based Prospective Study for Next Generation; PHC, public health center\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted conforming to the Declaration of Helsinki and the Ethical Guidelines for Medical and Biological Research Involving Human Subjects, and was initiated in each cohort by obtaining written informed consent from all participants at the time of study enrollment.\u0026nbsp;The individual study protocols were approved by the Institutional Review Board of Yamagata University Faculty of Medicine (#2019-175) and the National Cancer Center Japan (2011-186), and the pooled analysis protocol was approved by Yamagata University Faculty of Medicine (#2019-175) and the National Cancer Center Japan (2017-243).\u003cbr\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Data availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJPHC-NEXT and Yamagata studies are not publicly available because currently open only to researchers of Japanese nationality who meet the research requirements and are available from the corresponding author upon reasonable request. Investigators planning to access both study data must receive approval from relevant committees. For JPHC-NEXT, approval is required from both the JPHC-NEXT Steering Committee (SC) and the Institutional Review Board (IRB) of the National Cancer Center (NCC). Researchers must submit a Project Protocol (including research question, objectives, background, design, and analysis plan) for review by the JPHC-NEXT SC. Similarly, the Yamagata Study requires approval from the Cohort Steering Committee and the Institute's Steering Committee at the Yamagata University Well-Being Institute, with additional approval from the School of Medicine Ethics Review Committee for post-approval data. Requests can be made by contacting the JPHC SC directly ([email protected]) or contacting the Cohort Management Promotion Department ([email protected]) for information on applying for the Yamagata Study.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eAuthor’s contributions: MI responsible for the concept and design of the study and supervised the project. A.O., S.T., N.S., A.G., S.T., I.M., K.Y., Y.S., Y.A. and T.Y. contributed to data acquisition. A.O., N.S. and M.I. contributed to the analysis and interpretation of data. A.O. and M.I. drafted the manuscript. S.T., N.S., A.G., S.T., I.M., K.Y., Y.S., Y.A., T.K., Y.U., E.S., T.Y., M.I. and M.I. critically revised the manuscript for important intellectual content. All authors reviewed the manuscripts and contributed to the revision.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eWe appreciate all participants and staff members in each study area for their efforts in conducting the baseline and follow-up surveys.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by the National Cancer Center Research and Development Fund [23-A-31(toku), 26-A-2, 29-A-4] (since 2011), Research and Development by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (2011–2013), and by Practical Research for Innovative Cancer Control, Japan Cancer Research Project, Japan Agency for Medical Research and Development (AMED) (17ck0106277h0001,18ck0106277h0002,19ck0106277h0003,20ck0106561h0001,20ck0106561h0001RR,21ck0106561h0002,21ck0106561h0002RR,22ck0106561h0003, 22ck0106561h0003RR), and in part by the Japan Society for the Promotion of Science KAKENHI Grant Number JP20K08350 for the Yamaga Cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor’s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMI responsible for the concept and design of the study and supervised the project. AO, ST, NS, AG, ST, IM, KY, YS, YA and TY contributed to data acquisition. AO, NS and MI contributed to the analysis and interpretation of data. AO and MI drafted the manuscript. ST, NS, AG, ST, IM, KY, YS, YA, TK, YU, ES, TY, MI and MI critically revised the manuscript for important intellectual content. All authors reviewed the manuscripts and contributed to the revision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of conflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-263.\u003c/li\u003e\n \u003cli\u003eFerlay J EM, Lam F, Laversanne M, Colombet M, Mery L, Pi\u0026ntilde;eros M, Znaor A, Soerjomataram I, Bray F. Global Cancer Observatory: Cancer Today (version 1.1). Lyon, France: International Agency for Research on Cancer., 2024,accessed[02 Aug 2024].\u003c/li\u003e\n \u003cli\u003eCancer WIAfRo. IARC monographs on the identification of carcinogenic hazards to humans, 2022.\u003c/li\u003e\n \u003cli\u003eInoue M. Changing epidemiology of Helicobacter pylori in Japan. Gastric Cancer 2017;20:3-7.\u003c/li\u003e\n \u003cli\u003eCharvat H, Sasazuki S, Inoue M, et al. Prediction of the 10-year probability of gastric cancer occurrence in the Japanese population: the JPHC study cohort II. Int J Cancer 2016;138:320-31.\u003c/li\u003e\n \u003cli\u003eSasazuki S, Inoue M, Iwasaki M, et al. Effect of Helicobacter pylori infection combined with CagA and pepsinogen status on gastric cancer development among Japanese men and women: a nested case-control study. Cancer Epidemiol Biomarkers Prev 2006;15:1341-7.\u003c/li\u003e\n \u003cli\u003eSuzuki H, Mori H. World trends for H. pylori eradication therapy and gastric cancer prevention strategy by H. pylori test-and-treat. J Gastroenterol 2018;53:354-361.\u003c/li\u003e\n \u003cli\u003eLee YC, Chiang TH, Chou CK, et al. Association Between Helicobacter pylori Eradication and Gastric Cancer Incidence: A Systematic Review and Meta-analysis. Gastroenterology 2016;150:1113-1124.e5.\u003c/li\u003e\n \u003cli\u003eLin Y, Kawai S, Sasakabe T, et al. Effects of Helicobacter pylori eradication on gastric cancer incidence in the Japanese population: a systematic evidence review. Jpn J Clin Oncol 2021;51:1158-1170.\u003c/li\u003e\n \u003cli\u003eNarimatsu H. Constructing a contemporary gene-environmental cohort: study design of the Yamagata Molecular Epidemiological Cohort Study. J Hum Genet 2013;58:54-6.\u003c/li\u003e\n \u003cli\u003eSawada N, Iwasaki M, Yamaji T, et al. The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT): Study Design and Participants. J Epidemiol 2020;30:46-54.\u003c/li\u003e\n \u003cli\u003eDinis-Ribeiro M, Yamaki G, Miki K, et al. Meta-analysis on the validity of pepsinogen test for gastric carcinoma, dysplasia or chronic atrophic gastritis screening. J Med Screen 2004;11:141-7.\u003c/li\u003e\n \u003cli\u003eSasaki Y, Abe Y, Shoji M, et al. Reliability of self-reported questionnaire for epidemiological investigation of Helicobacter pylori eradication in a population-based cohort study. Sci Rep 2021;11:15605.\u003c/li\u003e\n \u003cli\u003eKihara T, Yamagishi K, Imatoh T, et al. Validity of self-reported Helicobacter pylori eradication treatment from questionnaire and interview surveys of the JPHC-NEXT study: comparison with prescription history from insurance claims data. J Epidemiol 2024.\u003c/li\u003e\n \u003cli\u003eFritz A, Percy, Constance, Jack, Andrew, Shanmugaratnam, Kanagaratnam, Sobin, Leslie H. et al. International classification of diseases for oncology, 3rd ed.: World Health Organization, 2000.\u003c/li\u003e\n \u003cli\u003eSauvaget C, Nagano J, Hayashi M, et al. Vegetables and fruit intake and cancer mortality in the Hiroshima/Nagasaki Life Span Study. Br J Cancer 2003;88:689-94.\u003c/li\u003e\n \u003cli\u003eNozaki K, Shimizu N, Ikehara Y, et al. Effect of early eradication on Helicobacter pylori-related gastric carcinogenesis in Mongolian gerbils. Cancer Sci 2003;94:235-9.\u003c/li\u003e\n \u003cli\u003eTake S, Mizuno M, Ishiki K, et al. The long-term risk of gastric cancer after the successful eradication of Helicobacter pylori. J Gastroenterol 2011;46:318-24.\u003c/li\u003e\n \u003cli\u003eMaeda M, Moro H, Ushijima T. Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway. Gastric Cancer 2017;20:8-15.\u003c/li\u003e\n \u003cli\u003eNakajima T, Maekita T, Oda I, et al. Higher methylation levels in gastric mucosae significantly correlate with higher risk of gastric cancers. Cancer Epidemiol Biomarkers Prev 2006;15:2317-21.\u003c/li\u003e\n \u003cli\u003eImai S, Ooki T, Murata-Kamiya N, et al. Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis. Cell Host Microbe 2021;29:941-958.e10.\u003c/li\u003e\n \u003cli\u003eTsugawa H, Suzuki H, Saya H, et al. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe 2012;12:764-77.\u003c/li\u003e\n \u003cli\u003eDinis-Ribeiro M, Areia M, de Vries AC, et al. Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy 2012;44:74-94.\u003c/li\u003e\n \u003cli\u003eHiroi S, Sugano K, Tanaka S, et al. Impact of health insurance coverage for Helicobacter pylori gastritis on the trends in eradication therapy in Japan: retrospective observational study and simulation study based on real-world data. BMJ Open 2017;7:e015855.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gastric cancer, Helicobacter pylori, atrophic gastritis, eradication, prospective cohort study, Japan","lastPublishedDoi":"10.21203/rs.3.rs-5036019/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5036019/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eHelicobacter pylori \u003c/em\u003e(\u003cem\u003eH. pylori) \u003c/em\u003einfection is the established cause of gastric cancer. Although \u003cem\u003eH. pylori \u003c/em\u003eeradication is suggested to decrease gastric cancer risk, this has not been fully investigated in general populations. This analysis included 48,530 Japanese men and women aged 40-74 years from four cohort studies. At baseline, the participants provided a self-reported eradication history, and serum anti-\u003cem\u003eH. pylori\u003c/em\u003e IgG titers and the atrophic gastritis (AG) severity. We examined the association between eradication history and gastric cancer risk with consideration to \u003cem\u003eH. pylori\u003c/em\u003e positivity and AG by Cox proportional hazards regression models. From 2010 to 2018 (average 5.8 years), 649 gastric cancer cases were diagnosed. Compared with those who were negative for both\u003cem\u003e H. pylori\u003c/em\u003e and AG as reference, gastric cancer risk was 5.89 times higher (95%CI: 4.41-7.87) in those who were \u003cem\u003eH. pylori \u003c/em\u003epositive and/or AG and with no eradication at baseline. Gastric cancer risk among those who underwent eradication before baseline decreased after a temporal increase in risk following eradication (baseline to \u0026lt;1y: HR 1.74, 95%CI 1.18-2.57; 1y to \u0026lt;6y: HR 0.81, 95%CI 0.59-1.11; ≥6y: HR 0.44, 95%CI 0.28-0.68). In a large Japanese general population, \u003cem\u003eH. pylori\u003c/em\u003eeradication was associated with long-term reduction in gastric cancer risk.\u003c/p\u003e","manuscriptTitle":"Helicobacter pylori eradication and gastric cancer prevention: Pooled analysis of large-scale cohort studies in Japan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-25 16:15:46","doi":"10.21203/rs.3.rs-5036019/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-30T10:55:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-19T18:48:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-14T02:38:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"270181685305515569214552287999613712565","date":"2024-09-13T21:09:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"221234022209751865507555111669252185449","date":"2024-09-13T20:33:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-13T12:54:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-13T12:36:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-09-10T17:54:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-09T10:18:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-09-05T07:20:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"28f37a07-7cf3-4916-9229-0599f17d6859","owner":[],"postedDate":"November 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":38360158,"name":"Health sciences/Medical research/Epidemiology"},{"id":38360159,"name":"Health sciences/Oncology/Cancer/Cancer prevention"},{"id":38360160,"name":"Health sciences/Oncology/Cancer/Cancer screening"},{"id":38360161,"name":"Health sciences/Oncology/Cancer/Gastrointestinal cancer/Gastric cancer"},{"id":38360162,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-07-07T16:16:36+00:00","versionOfRecord":{"articleIdentity":"rs-5036019","link":"https://doi.org/10.1038/s41598-025-00713-z","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-01 15:58:28","publishedOnDateReadable":"July 1st, 2025"},"versionCreatedAt":"2024-11-25 16:15:46","video":"","vorDoi":"10.1038/s41598-025-00713-z","vorDoiUrl":"https://doi.org/10.1038/s41598-025-00713-z","workflowStages":[]},"version":"v1","identity":"rs-5036019","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5036019","identity":"rs-5036019","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}