Korean J Gastroenterol.  2023 Oct;82(4):171-179. 10.4166/kjg.2023.097.

Helicobacter pylori-associated Chronic Atrophic Gastritis and Progression of Gastric Carcinogenesis

• Lim NR
• Chung WC

• KMID: 2547287
• DOI: http://doi.org/10.4166/kjg.2023.097

Abstract

Chronic inflammation due to a Helicobacter pylori (H. pylori) infection is a representative cause of gastric cancer that can promote gastric carcinogenesis by abnormally activating immune cells and increasing the inflammatory cytokines levels. H. pylori infections directly cause DNA double-strand breaks in gastric epithelial cells and genetic damage by increasing the enzymatic activity of cytidine deaminase. Eventually, gastric cancer is induced through dysplasia. Hypermethylation of tumor suppressor genes is an important cause of gastric cancer because of a H. pylori infection. In addition, the changes in gastric microbiota and the mucosal inflammatory changes associated with a co-infection with the Epstein-Barr virus are associated with gastric cancer development. DNA damage induced by H. pylori and the subsequent responses of gastric stem cells have implications for gastric carcinogenesis. Although the pathogenesis of H. pylori has been established, many uncertainties remain, requiring more study.

Keyword

Helicobacter pylori; Inflammation; Gastric cancer

Figure

• 

  Fig. 1 Metachronous gastric cancer after Helicobacter pylori eradication. (A) A 2.0 cm elevated mucosal lesion with a central depression (arrow) is identified on the anterior wall of the proximal antrum on the initial endoscopy. After endoscopic submucosal dissection, successful Helicobacter pylori is performed. (B) After six years of endoscopic treatment, surveillance endoscopy shows a surgical scar on the anterior wall of the proximal antrum. A 1.4 cm elevated mucosal lesion with central depression is shown on the greater curvature side of the high body. It is a metachronous lesion.

Reference

1. Hooi JKY, Lai WY, Ng WK, et al. 2017; Global prevalence of Helicobacter pylori infection: Systematic review and meta-analysis. Gastroenterology. 153:420–429. DOI: 10.1053/j.gastro.2017.04.022. PMID: 28456631.

2. Uemura N, Okamoto S, Yamamoto S, et al. 2001; Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 345:784–789. DOI: 10.1056/NEJMoa001999. PMID: 11556297.

3. Ohata H, Kitauchi S, Yoshimura N, et al. 2004; Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer. 109:138–143. DOI: 10.1002/ijc.11680. PMID: 14735480.

4. Kawamura M, Uedo N, Koike T, et al. 2022; Kyoto classification risk scoring system and endoscopic grading of gastric intestinal metaplasia for gastric cancer: Multicenter observation study in Japan. Dig Endosc. 34:508–516. DOI: 10.1111/den.14114. PMID: 34415621.

5. Kim GH. 2023; Clinical Application of the Kyoto classification of gastritis. Korean J Helicobacter Up Gastrointest Res. 23:89–98. DOI: 10.7704/kjhugr.2023.0013.

6. Senchukova MA. 2022; Helicobacter pylori and gastric cancer progression. Curr Microbiol. 79:383. DOI: 10.1007/s00284-022-03089-9. PMID: 36329283.

7. Dooyema SDR, Noto JM, Wroblewski LE, et al. 2022; Helicobacter pylori actively suppresses innate immune nucleic acid receptors. Gut Microbes. 14:2105102. DOI: 10.1080/19490976.2022.2105102. PMID: 35905376. PMCID: PMC9341374.

8. Maubach G, Vieth M, Boccellato F, Naumann M. 2022; Helicobacter pylori-induced NF-κB: trailblazer for gastric pathophysiology. Trends Mol Med. 28:210–222. DOI: 10.1016/j.molmed.2021.12.005. PMID: 35012886.

9. Araújo GRL, Marques HS, Santos MLC, et al. 2022; Helicobacter pylori infection: How does age influence the inflammatory pattern? World J Gastroenterol. 28:402–411. DOI: 10.3748/wjg.v28.i4.402. PMID: 35125826. PMCID: PMC8790560.

10. Yan L, Chen Y, Chen F, et al. 2022; Effect of Helicobacter pylori eradication on gastric cancer prevention: Updated report from a randomized controlled trial with 26.5 years of follow-up. Gastroenterology. 163:154–162.e3. DOI: 10.1053/j.gastro.2022.03.039. PMID: 35364066.

11. Hoffmann W. 2008; Regeneration of the gastric mucosa and its glands from stem cells. Curr Med Chem. 15:3133–3144. DOI: 10.2174/092986708786848587. PMID: 19075658.

12. Suganuma M, Watanabe T, Sueoka E, Lim IK, Fujiki H. 2021; Role of TNF-α-inducing protein secreted by Helicobacter pylori as a tumor promoter in gastric cancer and emerging preventive strategies. Toxins (Basel). 13:181. DOI: 10.3390/toxins13030181. PMID: 33804551. PMCID: PMC7999756.

13. Di Mario F, Crafa P, Barchi A, et al. 2022; Pepsinogen II in gastritis and Helicobacter pylori infection. Helicobacter. 27:e12872. DOI: 10.1111/hel.12872. PMID: 34997989.

14. Goldenring JR. 2018; Pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage and spasmolytic polypeptide-expressing metaplasia: reparative lineages in the gastrointestinal mucosa. J Pathol. 245:132–137. DOI: 10.1002/path.5066. PMID: 29508389. PMCID: PMC6026529.

15. Yang H, Zhou X, Hu B. 2022; The 'reversibility' of chronic atrophic gastritis after the eradication of Helicobacter pylori. Postgrad Med. 134:474–479. DOI: 10.1080/00325481.2022.2063604. PMID: 35382697.

16. Nephew KP, Huang TH. 2003; Epigenetic gene silencing in cancer initiation and progression. Cancer Lett. 190:125–133. DOI: 10.1016/S0304-3835(02)00511-6. PMID: 12565166.

17. Esteller M, Herman JG. 2002; Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J Pathol. 196:1–7. DOI: 10.1002/path.1024. PMID: 11748635.

18. Chan AO, Lam SK, Wong BC, et al. 2003; Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer. Gut. 52:502–506. DOI: 10.1136/gut.52.4.502. PMID: 12631658. PMCID: PMC1773595.

19. Leung WK, Man EP, Yu J, et al. 2006; Effects of Helicobacter pylori eradication on methylation status of E-cadherin gene in noncancerous stomach. Clin Cancer Res. 12:3216–3221. DOI: 10.1158/1078-0432.CCR-05-2442. PMID: 16707623.

20. Grady WM, Willis J, Guilford PJ, et al. 2000; Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet. 26:16–17. DOI: 10.1038/79120. PMID: 10973239.

21. Tamura G, Yin J, Wang S, et al. 2000; E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. J Natl Cancer Inst. 92:569–573. DOI: 10.1093/jnci/92.7.569. PMID: 10749913.

22. Shi J, Zhang G, Yao D, et al. 2012; Prognostic significance of aberrant gene methylation in gastric cancer. Am J Cancer Res. 2:116–129.

23. Miao R, Guo X, Zhi Q, et al. 2013; VEZT, a novel putative tumor suppressor, suppresses the growth and tumorigenicity of gastric cancer. PLoS One. 8:e74409. DOI: 10.1371/journal.pone.0074409. PMID: 24069310. PMCID: PMC3775783.

24. Wang Y, Huang LH, Xu CX, et al. 2014; Connexin 32 and 43 promoter methylation in Helicobacter pylori-associated gastric tumorigenesis. World J Gastroenterol. 20:11770–11779. DOI: 10.3748/wjg.v20.i33.11770. PMID: 25206281. PMCID: PMC4155367.

25. Kaneda A, Wakazono K, Tsukamoto T, et al. 2004; Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. Cancer Res. 64:6410–6415. DOI: 10.1158/0008-5472.CAN-04-1543. PMID: 15374948.

26. Kang GH, Lee S, Cho NY, et al. 2008; DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest. 88:161–170. DOI: 10.1038/labinvest.3700707. PMID: 18158559.

27. Nardone G, Compare D. 2008; Epigenetic alterations due to diet and Helicobacter pylori infection in gastric carcinogenesis. Expert Rev Gastroenterol Hepatol. 2:243–248. DOI: 10.1586/17474124.2.2.243. PMID: 19072359.

28. Shu XS, Geng H, Li L, et al. 2011; The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors. PLoS One. 6:e27346. DOI: 10.1371/journal.pone.0027346. PMID: 22087297. PMCID: PMC3210799.

29. Joo JK, Kim SH, Kim HG, et al. 2010; CpG methylation of transcription factor 4 in gastric carcinoma. Ann Surg Oncol. 17:3344–3353. DOI: 10.1245/s10434-010-1131-z. PMID: 20585880.

30. Perri F, Cotugno R, Piepoli A, et al. 2007; Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication. Am J Gastroenterol. 102:1361–1371. DOI: 10.1111/j.1572-0241.2007.01284.x. PMID: 17509026.

31. Sepulveda AR, Yao Y, Yan W, et al. 2010; CpG methylation and reduced expression of O6-methylguanine DNA methyltransferase is associated with Helicobacter pylori infection. Gastroenterology. 138:1836–1844. DOI: 10.1053/j.gastro.2009.12.042. PMID: 20044995.

32. Kim KK, Kim HB. 2009; Protein interaction network related to Helicobacter pylori infection response. World J Gastroenterol. 15:4518–4528. DOI: 10.3748/wjg.15.4518. PMID: 19777610. PMCID: PMC2751996.

33. Sugita H, Iida S, Inokuchi M, et al. 2011; Methylation of BNIP3 and DAPK indicates lower response to chemotherapy and poor prognosis in gastric cancer. Oncol Rep. 25:513–518. DOI: 10.3892/or.2010.1085. PMID: 21152877.

34. Yan J, Zhang M, Zhang J, Chen X, Zhang X. 2011; Helicobacter pylori infection promotes methylation of WWOX gene in human gastric cancer. Biochem Biophys Res Commun. 408:99–102. DOI: 10.1016/j.bbrc.2011.03.127. PMID: 21466786.

35. Kang GH, Lee S, Kim JS, Jung HY. 2003; Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis. Lab Invest. 83:635–641. DOI: 10.1097/01.LAB.0000067481.08984.3F. PMID: 12746473.

36. Yu J, Cheng YY, Tao Q, et al. 2009; Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer. Gastroenterology. 136:640–651. e1. DOI: 10.1053/j.gastro.2008.10.050. PMID: 19084528.

37. Hu X, Sui X, Li L, et al. 2013; Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol. 229:62–73. DOI: 10.1002/path.4093. PMID: 22926751.

38. Cheng YY, Yu J, Wong YP, et al. 2007; Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer. Br J Cancer. 97:895–901. DOI: 10.1038/sj.bjc.6603968. PMID: 17848950. PMCID: PMC2360406.

39. Peterson AJ, Menheniott TR, O'Connor L, et al. 2010; Helicobacter pylori infection promotes methylation and silencing of trefoil factor 2, leading to gastric tumor development in mice and humans. Gastroenterology. 139:2005–2017. DOI: 10.1053/j.gastro.2010.08.043. PMID: 20801119. PMCID: PMC3970568.

40. Katayama Y, Takahashi M, Kuwayama H. 2009; Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochem Biophys Res Commun. 388:496–500. DOI: 10.1016/j.bbrc.2009.08.003. PMID: 19665002.

41. Lu XX, Yu JL, Ying LS, et al. 2012; Stepwise cumulation of RUNX3 methylation mediated by Helicobacter pylori infection contributes to gastric carcinoma progression. Cancer. 118:5507–5517. DOI: 10.1002/cncr.27604. PMID: 22576578.

42. Wang LJ, Jin HC, Wang X, et al. 2009; ZIC1 is downregulated through promoter hypermethylation in gastric cancer. Biochem Biophys Res Commun. 379:959–963. DOI: 10.1016/j.bbrc.2008.12.180. PMID: 19135984.

43. Cheng AS, Li MS, Kang W, et al. 2013; Helicobacter pylori causes epigenetic dysregulation of FOXD3 to promote gastric carcinogenesis. Gastroenterology. 144:122–133.e9. DOI: 10.1053/j.gastro.2012.10.002. PMID: 23058321.

44. Bussière FI, Michel V, Mémet S, et al. 2010; H. pylori-induced promoter hypermethylation downregulates USF1 and USF2 transcription factor gene expression. Cell Microbiol. 12:1124–1133. DOI: 10.1111/j.1462-5822.2010.01457.x. PMID: 20180799.

45. Wen XZ, Akiyama Y, Pan KF, et al. 2010; Methylation of GATA-4 and GATA-5 and development of sporadic gastric carcinomas. World J Gastroenterol. 16:1201–1208. DOI: 10.3748/wjg.v16.i10.1201. PMID: 20222162. PMCID: PMC2839171.

46. Muhammad JS, Nanjo S, Ando T, et al. 2017; Autophagy impairment by Helicobacter pylori-induced methylation silencing of MAP1LC3Av1 promotes gastric carcinogenesis. Int J Cancer. 140:2272–2283. DOI: 10.1002/ijc.30657. PMID: 28214334.

47. Tanaka S, Nagashima H, Uotani T, Graham DY, Yamaoka Y. 2017; Autophagy-related genes in Helicobacter pylori infection. Helicobacter. 22:e12376. DOI: 10.1111/hel.12376. PMID: 28111844. PMCID: PMC5422124.

48. Wang H, Duan XL, Qi XL, et al. 2017; Concurrent hypermethylation of SFRP2 and DKK2 activates the Wnt/β-Catenin pathway and is associated with poor prognosis in patients with gastric cancer. Mol Cells. 40:45–53. DOI: 10.14348/molcells.2017.2245. PMID: 28152305. PMCID: PMC5303888.

49. Oshimo Y, Kuraoka K, Nakayama H, et al. 2004; Epigenetic inactivation of SOCS-1 by CpG island hypermethylation in human gastric carcinoma. Int J Cancer. 112:1003–1009. DOI: 10.1002/ijc.20521. PMID: 15386345.

50. Oue N, Mitani Y, Motoshita J, et al. 2006; Accumulation of DNA methylation is associated with tumor stage in gastric cancer. Cancer. 106:1250–1259. DOI: 10.1002/cncr.21754. PMID: 16475210.

51. Yu J, Tao Q, Cheng YY, et al. 2009; Promoter methylation of the Wnt/beta-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer. Cancer. 115:49–60. DOI: 10.1002/cncr.23989. PMID: 19051296.

52. Hibi K, Goto T, Kitamura YH, et al. 2010; Methylation of the TFPI2 gene is frequently detected in advanced gastric carcinoma. Anticancer Res. 30:4131–4133.

53. Choi JM, Kim SG. 2021; Effect of Helicobacter pylori eradication on epigenetic changes in gastric cancer-related genes. Korean J Helicobacter Up Gastrointest Res. 21:256–266. DOI: 10.7704/kjhugr.2021.0042.

54. Tahara T, Arisawa T. 2015; DNA methylation as a molecular biomarker in gastric cancer. Epigenomics. 7:475–486. DOI: 10.2217/epi.15.4. PMID: 26077432.

55. Lee JR, Chung WC, Kim JD, et al. 2011; Differential LINE-1 hypomethylation of gastric low-grade dysplasia from high grade dysplasia and intramucosal cancer. Gut Liver. 5:149–153. DOI: 10.5009/gnl.2011.5.2.149. PMID: 21814593. PMCID: PMC3140658.

56. Kim EJ, Chung WC, Kim DB, et al. 2016; Long interspersed nuclear element (LINE)-1 methylation level as a molecular marker of early gastric cancer. Dig Liver Dis. 48:1093–1097. DOI: 10.1016/j.dld.2016.06.002. PMID: 27375206.

57. Capparelli R, Iannelli D. 2022; Epigenetics and Helicobacter pylori. Int J Mol Sci. 23:1759. DOI: 10.3390/ijms23031759. PMID: 35163679. PMCID: PMC8836069.

58. Kubota Y, Tanabe S, Azuma M, et al. 2021; Predictive significance of promoter DNA methylation of cysteine dioxygenase type 1 (CDO1) in metachronous gastric cancer. J Gastric Cancer. 21:379–391. DOI: 10.5230/jgc.2021.21.e35. PMID: 35079440. PMCID: PMC8753284.

59. Huang G, Wang S, Wang J, et al. 2022; Bile reflux alters the profile of the gastric mucosa microbiota. Front Cell Infect Microbiol. 12:940687. DOI: 10.3389/fcimb.2022.940687. PMID: 36159635. PMCID: PMC9500345.

60. Bessède E, Mégraud F. 2022; Microbiota and gastric cancer. Semin Cancer Biol. 86:11–17. DOI: 10.1016/j.semcancer.2022.05.001. PMID: 35533800.

61. Guo Y, Cao XS, Guo GY, Zhou MG, Yu B. 2022; Effect of Helicobacter pylori eradication on human gastric microbiota: A systematic review and meta-analysis. Front Cell Infect Microbiol. 12:899248. DOI: 10.3389/fcimb.2022.899248. PMID: 35601105. PMCID: PMC9114356.

62. Liu C, Ng SK, Ding Y, et al. 2022; Meta-analysis of mucosal microbiota reveals universal microbial signatures and dysbiosis in gastric carcinogenesis. Oncogene. 41:3599–3610. DOI: 10.1038/s41388-022-02377-9. PMID: 35680985. PMCID: PMC9270228.

63. Png CW, Lee WJJ, Chua SJ, et al. 2022; Mucosal microbiome associates with progression to gastric cancer. Theranostics. 12:48–58. DOI: 10.7150/thno.65302. PMID: 34987633. PMCID: PMC8690935.

64. Li Y, Jiang L, Li Z, et al. 2022; Differences in gastric microbiota and mucosal function between patients with chronic superficial gastritis and intestinal metaplasia. Front Microbiol. 13:950325. DOI: 10.3389/fmicb.2022.950325. PMID: 36466659. PMCID: PMC9712754.

65. Ignatova E, Seriak D, Fedyanin M, et al. 2020; Epstein-Barr virus-associated gastric cancer: disease that requires special approach. Gastric Cancer. 23:951–960. DOI: 10.1007/s10120-020-01095-z. PMID: 32514646.

66. Song HJ, Srivastava A, Lee J, et al. 2010; Host inflammatory response predicts survival of patients with Epstein-Barr virus-associated gastric carcinoma. Gastroenterology. 139:84–92.e2. DOI: 10.1053/j.gastro.2010.04.002. PMID: 20398662.

67. Naseem M, Barzi A, Brezden-Masley C, et al. 2018; Outlooks on Epstein-Barr virus associated gastric cancer. Cancer Treat Rev. 66:15–22. DOI: 10.1016/j.ctrv.2018.03.006. PMID: 29631196. PMCID: PMC5964025.

68. Noh JH, Shin JY, Lee JH, et al. 2023; Clinical significance of Epstein-Barr Virus and Helicobacter pylori infection in gastric carcinoma. Gut Liver. 17:69–77. DOI: 10.5009/gnl210593. PMID: 35611669. PMCID: PMC9840931.

69. Lee JH, Kim S, Han S, et al. 2022; p57Kip2 imposes the reserve stem cell state of gastric chief cells. Cell Stem Cell. 29:826–839. e9. DOI: 10.1016/j.stem.2022.04.001. PMID: 35523142. PMCID: PMC9097776.

70. Liabeuf D, Oshima M, Stange DE, Sigal M. 2022; Stem cells, Helicobacter pylori, and mutational landscape: utility of preclinical models to understand carcinogenesis and to direct management of gastric cancer. Gastroenterology. 162:1067–1087. DOI: 10.1053/j.gastro.2021.12.252. PMID: 34942172.

71. He J, Hu W, Ouyang Q, et al. 2022; Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer. Cancer Lett. 542:215764. DOI: 10.1016/j.canlet.2022.215764. PMID: 35654291.

72. Uehara T, Ma D, Yao Y, et al. 2013; H. pylori infection is associated with DNA damage of Lgr5-positive epithelial stem cells in the stomach of patients with gastric cancer. Dig Dis Sci. 58:140–149. DOI: 10.1007/s10620-012-2360-8. PMID: 22945475. PMCID: PMC3816997.

73. Abe H, Ushiku T. 2022; Pathological diversity of gastric cancer from the viewpoint of background condition. Digestion. 103:45–53. DOI: 10.1159/000519337. PMID: 34628409.

74. Iwamuro M, Kusumoto C, Nakagawa M, et al. 2022; Endoscopic features of oxyntic gland adenoma and gastric adenocarcinoma of the fundic gland type differ between patients with and without Helicobacter pylori infection: a retrospective observational study. BMC Gastroenterol. 22:294. DOI: 10.1186/s12876-022-02368-w. PMID: 35692036. PMCID: PMC9188703.

75. Yamamoto Y, Fujisaki J, Omae M, Hirasawa T, Igarashi M. 2015; Helicobacter pylori-negative gastric cancer: characteristics and endoscopic findings. Dig Endosc. 27:551–561. DOI: 10.1111/den.12471. PMID: 25807972.

76. Yasuda T, Lee HS, Nam SY, et al. 2022; Non-Helicobacter pylori Helicobacter (NHPH) positive gastric cancer. Sci Rep. 12:4811. DOI: 10.1038/s41598-022-08962-y. PMID: 35314746. PMCID: PMC8938428.

77. Tsai KF, Liou JM, Chen MJ, et al. 2017; Distinct clinicopathological features and prognosis of Helicobacter pylori negative gastric cancer. PLoS One. 12:e0170942. DOI: 10.1371/journal.pone.0170942. PMID: 28152027. PMCID: PMC5289528.