H.pylori gastric adenocarcinoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Yamuna Kondapally, M.B.B.S[3]

Overview

H. pylori is a WHO/IARC group 1 (definite) carcinogen and the strongest known risk factor for non-cardia gastric adenocarcinoma, to which roughly 75–90% of cases are attributable.[1][2] Despite a global adult prevalence of approximately 43%, only about 1–3% of infected persons develop gastric cancer, reflecting the decisive influence of bacterial virulence genotype, host genetics, and environmental cofactors.[3][1]

Carcinogenesis proceeds by two convergent routes: decades-long chronic inflammation driving the stepwise histologic Correa cascade (chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → intestinal-type adenocarcinoma), and direct genotoxic and oncogenic signaling by injected bacterial effectors.[4][5] The pathophysiology is actionable: eradication interrupts the cascade and reduces cancer incidence and mortality, with the greatest benefit before atrophy and metaplasia develop.[6]

Pathophysiology

Correa cascade

Intestinal-type non-cardia gastric cancer follows a stepwise histologic sequence: normal mucosa → chronic non-atrophic gastritis → chronic atrophic gastritis with loss of acid-secreting parietal cells → intestinal metaplasia → dysplasia → invasive carcinoma.[7][8]

  • Atrophy and achlorhydria are the pivotal transition. Parietal cell loss raises intragastric pH, removing a defense against mutagenic colonization and permitting a dysbiotic, nitrosating gastric microbiota that sustains carcinogenesis even as H. pylori density falls in later stages — the "hit-and-run" concept.[3][4][9]
  • Intestinal metaplasia marks substantially elevated risk (annual progression to cancer on the order of 0.1–0.3%), and incomplete (type III) metaplasia carries higher progression risk than complete metaplasia. It is often regarded as a relative "point of no return" at which eradication benefit diminishes.[8][10]
  • Modern refinements. Single-cell and lineage-tracing data show non-linear, region-specific trajectories; in the corpus, oxyntic atrophy triggers spasmolytic polypeptide-expressing metaplasia (SPEM), and mutant isthmus progenitors can progress to dysplasia bypassing intestinal metaplasia. These refine rather than replace the tissue-level Correa sequence.[4]
  • Diffuse-type cancer generally lacks defined precursor lesions, arises at younger ages, and is linked to CDH1/E-cadherin loss; chronic inflammation does not appear to be required, implying distinct mechanisms.[5]

Bacterial virulence factors

A functional cag pathogenicity island (cag-PAI) encoding a type IV secretion system is the single most important determinant of a strain's pro-inflammatory and oncogenic potential.[3]

Factor Mechanism Cancer relevance
cag-PAI / T4SS Syringe-like apparatus injecting effectors into epithelial cells; also activates NF-κB independently of CagA Strongest strain-level determinant of severe gastritis and carcinoma
CagA oncoprotein Phosphorylated by Src/Abl kinases at C-terminal EPIYA motifs (EPIYA-A/B/C in Western strains; EPIYA-D in East Asian strains, which binds SHP2 more avidly); aberrantly activates SHP2–ERK/MAPK, PI3K–AKT and WNT/β-catenin; phosphorylation-independent binding of PAR1b and tight junction proteins disrupts epithelial polarity Confers multiple cancer hallmarks; drives epithelial–mesenchymal transition and a "hit-and-run" mode of transformation
VacA Present in nearly all strains; forms anion channels, induces mitochondrial dysfunction, apoptosis and autophagy, and suppresses T cell activation Risk is genotype-dependent; the s1/i1/m1 allelic combination is most strongly associated with gastric cancer
ADP-heptose CagA-independent effector delivered via the T4SS; activates ALPK1–TIFA–NF-κB signaling Major driver of initial mucosal inflammation (e.g. IL-8 release)
Adhesins (BabA, SabA, OipA) Strengthen binding to gastric epithelium Amplify IL-8 and β-catenin signaling and prolong colonization

[4][9][11][12]

Mechanisms of malignant transformation

  • Chronic inflammation. H. pylori activates NF-κB through TLRs, NOD-like receptors, lipopolysaccharide, peptidoglycan and CagA, sustaining IL-1β, IL-6, IL-8 and TNF-α production with a Th1-skewed response. The resulting reactive oxygen species and reactive nitrogen species create a mutagenic milieu and cause DNA damage, while chronic injury drives compensatory hyperproliferation and altered differentiation underlying metaplasia.[1][3]
  • Direct genotoxicity and transient "BRCAness". Infection induces DNA double-strand breaks in a T4SS-dependent manner and transiently impairs homologous recombination repair, producing error-prone repair and genomic instability. In a Japanese biobank analysis, carriers of germline pathogenic variants in homologous-recombination genes (ATM, BRCA1, BRCA2, PALB2) had a cumulative gastric cancer risk of 45.5% when H. pylori-infected versus under 5% when uninfected, demonstrating a true gene–infection interaction.[13]
  • Epigenetic reprogramming. Inflammation induces DNA methyltransferases and aberrant promoter hypermethylation of tumor suppressor genes (CDKN2A/p16, MLH1, CDH1), along with altered histone marks and non-coding RNAs; CagA/NF-κB signaling drives CDX1/CDX2-dependent intestinal transdifferentiation.[1][5]
  • Stem-cell and niche remodeling. Gland-associated bacteria colonize deep gastric glands and activate and expand LGR5+ stem cells via the stromal RSPO3–LGR4/LGR5 axis, with YAP activation and collapse of BMP signaling expanding a transformation-susceptible compartment. Stromal IL-1β signaling reprograms the antral niche toward a fetal-like regenerative state through a COX2/PGE2 intermediate.[14][15][16]
  • Dysbiosis and field cancerization. Achlorhydria permits overgrowth of nitrosating oral and intestinal commensals that generate N-nitroso compounds and perpetuate transformation; molecular alterations accumulate even in histologically normal mucosa.[4][17]

Host and environmental modifiers

  • Host genetics. Pro-inflammatory, acid-suppressing polymorphisms of the IL-1 gene cluster amplify risk by promoting hypochlorhydria and atrophy; IL-1B-511T carriers homozygous for IL-1RN*2 have elevated risk.[18] Combined high-risk host and high-risk bacterial genotypes (e.g. cagA-positive/vacA s1 strains with IL-1B-511T) raise risk far above either factor alone, by up to roughly 87-fold in the original Portuguese series.[19] Meta-analysis confirms that the IL-1B effect is confined to the H. pylori-infected subgroup.[20]
  • Environment and lifestyle. High dietary salt, salted, smoked and pickled foods, N-nitroso compounds, tobacco and alcohol potentiate the cascade but are subordinate to H. pylori.[1][3]
  • EBV accounts for 5–10% of gastric cancers through a distinct, hypermethylated molecular subtype independent of H. pylori.[1]

Topography of gastritis and disease phenotype

Antral-predominant gastritis with preserved or increased acid output predisposes to duodenal ulcer, whereas corpus-predominant or pangastritis with hypochlorhydria and atrophy predisposes to carcinoma. Severe atrophic gastritis, corpus-predominant gastritis, and intestinal metaplasia identify patients at highest risk for intestinal-type gastric carcinoma.[21][18]

Clinically actionable implications

  • Eradication prevents cancer. Pooled randomized trials show that eradication reduces gastric cancer incidence in healthy infected individuals (RR 0.64; 95% CI 0.48–0.84) and metachronous cancer after endoscopic mucosal resection (RR 0.52; 95% CI 0.38–0.71), and reduces gastric cancer mortality (RR 0.78; 95% CI 0.62–0.98).[6]
  • Treat early. Benefit is greatest before atrophy or intestinal metaplasia are established.[22]
  • Continue surveillance after eradication once intestinal metaplasia or dysplasia is present, because eradication does not reliably abolish risk at that stage.[10][22]
  • Do not use serology to confirm eradication, as it cannot distinguish active from past infection; bacterial load also falls with progressive atrophy, producing false-negative histology in advanced disease.[10]

Areas of uncertainty

  • Whether intestinal metaplasia represents a true point of no return, and whether it raises risk independently of atrophy, remains debated; eradication benefit after metaplasia or dysplasia is inconsistent.[8][10]
  • Nearly all eradication trials were conducted in East Asia; direct randomized data from other regions, including the United States, are lacking.[6]
  • Diffuse-type pathogenesis remains poorly defined and may not require the inflammatory cascade.[5]
  • Routine bacterial and host genotyping refines risk estimation in research settings but is not standard of care.[3]


References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Zavros Y, Merchant JL (2022). "The immune microenvironment in gastric adenocarcinoma". Nat Rev Gastroenterol Hepatol. 19 (7): 451–467. doi:10.1038/s41575-022-00591-0. PMID 35288702 Check |pmid= value (help).
  2. ↑ Plummer M, Franceschi S, Vignat J, Forman D, de Martel C (2015). "Global burden of gastric cancer attributable to Helicobacter pylori". Int J Cancer. 136 (2): 487–490. doi:10.1002/ijc.28999. PMID 24889903.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Malfertheiner P, Camargo MC, El-Omar E, Liou JM, Peek R, Schulz C, Smith SI, Suerbaum S (2023). "Helicobacter pylori infection". Nat Rev Dis Primers. 9 (1): 19. doi:10.1038/s41572-023-00431-8. PMID 37081005 Check |pmid= value (help).
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Wizenty J, Sigal M (2025). "Helicobacter pylori, microbiota and gastric cancer - principles of microorganism-driven carcinogenesis". Nat Rev Gastroenterol Hepatol. 22 (5): 296–313. doi:10.1038/s41575-025-01042-2.
  5. ↑ 5.0 5.1 5.2 5.3 Yeoh KG, Tan P (2022). "Mapping the genomic diaspora of gastric cancer". Nat Rev Cancer. 22 (2): 71–84. doi:10.1038/s41568-021-00412-7. PMID 34702982 Check |pmid= value (help).
  6. ↑ 6.0 6.1 6.2 Ford AC, Yuan Y, Park JY; et al. (2025). "Eradication Therapy to Prevent Gastric Cancer in Helicobacter pylori-Positive Individuals: Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Studies". Gastroenterology. 169 (2): 261–276. PMID 39824392 Check |pmid= value (help).
  7. ↑ Correa P (1992). "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention". Cancer Res. 52 (24): 6735–40. PMID 1458460.
  8. ↑ 8.0 8.1 8.2 Gawron AJ, Shah SC, Altayar O, Davitkov P, Morgan D, Turner K, Mustafa RA (2020). "AGA Technical Review on Gastric Intestinal Metaplasia-Natural History and Clinical Outcomes". Gastroenterology. 158 (3): 705–731.e5. doi:10.1053/j.gastro.2019.12.001. PMID 31816300.
  9. ↑ 9.0 9.1 Hatakeyama M (2019). "Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis". Cell Mol Immunol. doi:10.1038/s41423-019-0339-5.
  10. ↑ 10.0 10.1 10.2 10.3 Moss SF, Shah SC, Tan MC, El-Serag HB (2024). "Evolving Concepts in Helicobacter pylori Management". Gastroenterology. 166 (2): 267–283. doi:10.1053/j.gastro.2023.09.047.
  11. ↑ McClain MS, Beckett AC, Cover TL (2017). "Helicobacter pylori Vacuolating Toxin and Gastric Cancer". Toxins (Basel). 9 (10): 316. doi:10.3390/toxins9100316.
  12. ↑ Pfannkuch L, Hurwitz R, Traulsen J; et al. (2019). "ADP heptose, a novel pathogen-associated molecular pattern identified in Helicobacter pylori". FASEB J. 33 (8): 9087–9099. doi:10.1096/fj.201802555R. PMID 31075211.
  13. ↑ Usui Y, Taniyama Y, Endo M; et al. (2023). "Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer". N Engl J Med. 388 (13): 1181–1190. doi:10.1056/NEJMoa2211807. PMID 36988593 Check |pmid= value (help).
  14. ↑ Sigal M, Rothenberg ME, Logan CY; et al. (2015). "Helicobacter pylori activates and expands Lgr5(+) stem cells through direct colonization of the gastric glands". Gastroenterology. 148 (7): 1392–1404.e21. doi:10.1053/j.gastro.2015.02.049. PMID 25725293.
  15. ↑ Fischer AS, Müllerke S, Arnold A; et al. (2022). "R-spondin/YAP axis promotes gastric oxyntic gland regeneration and Helicobacter pylori-associated metaplasia in mice". J Clin Invest. 132 (21): e151363. doi:10.1172/JCI151363. PMID 36099044 Check |pmid= value (help).
  16. ↑ Beccaceci G, Müllerke S, Berger H; et al. (2026). "Helicobacter pylori triggers gastric mucosal remodeling toward a fetal-like transcriptional program via stromal IL-1β signaling". Nat Commun. 17: 9510. doi:10.1038/s41467-026-77520-1. PMID 42701138 Check |pmid= value (help).
  17. ↑ Abreu MT, Peek RM (2014). "Gastrointestinal malignancy and the microbiome". Gastroenterology. 146 (6): 1534–1546.e3. doi:10.1053/j.gastro.2014.01.001. PMID 24406471.
  18. ↑ 18.0 18.1 El-Omar EM, Carrington M, Chow WH; et al. (2000). "Interleukin-1 polymorphisms associated with increased risk of gastric cancer". Nature. 404 (6776): 398–402. doi:10.1038/35006081. PMID 10746728.
  19. ↑ Figueiredo C, Machado JC, Pharoah P; et al. (2002). "Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma". J Natl Cancer Inst. 94 (22): 1680–1687.
  20. ↑ Ying HY, Yu BW, Yang Z; et al. (2016). "Interleukin-1B 31 C>T polymorphism combined with Helicobacter pylori-modified gastric cancer susceptibility: evidence from 37 studies". J Cell Mol Med. 20 (3): 526–536. doi:10.1111/jcmm.12737. PMID 26805397.
  21. ↑ Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M; et al. (2001). "Helicobacter pylori infection and the development of gastric cancer". N Engl J Med. 345 (11): 784–9. doi:10.1056/NEJMoa001999. PMID 11556297.
  22. ↑ 22.0 22.1 Shah SC, Wang AY, Wallace MB, Hwang JH (2025). "AGA Clinical Practice Update on Screening and Surveillance in Individuals at Increased Risk for Gastric Cancer in the United States: Expert Review". Gastroenterology. PMID 39718517 Check |pmid= value (help).
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