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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] Omer Kamal, M.D.[3], Mohammed Abdelwahed M.D[4]

Overview

Gastric adenocarcinoma results from an interaction between chronic infection, environmental and dietary exposures, host genetic susceptibility, and, in a small minority, high-penetrance germline variants. Chronic Helicobacter pylori infection, an IARC group 1 carcinogen, is the dominant modifiable cause. It accounts for approximately 75% of attributable risk overall and approximately 90% of non-cardia (distal) cancers.[1][2] Most intestinal-type cancers arise through the stepwise Correa cascade (chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma). Diffuse-type cancers frequently arise without a recognizable precancerous lesion. When diffuse-type cancer is hereditary, it is driven by germline CDH1 (E-cadherin) inactivation.[3] About 10% of cases show familial clustering, but only about 1–3% are attributable to a known heritable germline variant.[4] The TCGA molecular classification (EBV-positive, MSI, genomically stable, chromosomal instability) has superseded older, undifferentiated oncogene lists as the framework for molecular etiology.[5]

Causes

Infectious Causes

Helicobacter pylori

  • H. pylori is the single most important and most modifiable cause of gastric adenocarcinoma.
    • IARC classified it as a group 1 carcinogen in 1994 and reaffirmed this classification in 2009.[2][6]
  • Attributable risk: approximately 75% of global gastric cancer and approximately 90% of non-cardia cancers. In Japan, fewer than 1% of gastric adenocarcinomas are considered unrelated to H. pylori.[1][7]
  • Anatomic specificity: the association is strong for non-cardia cancer (pooled OR approximately 2.97) and essentially null for cardia cancer (OR approximately 0.99).[8]
  • Test method affects measured risk: serology reflects lifetime infection and yields higher odds ratios than histology. Histology underestimates infection when atrophic gastritis has reduced the bacterial load.[2]
  • Low absolute risk per infected person: about 44% of adults worldwide are infected, but only about 1–3% of infected individuals develop gastric cancer. Strain virulence, host genetics, and co-exposures modulate this risk.[1][9]
  • Mechanism (Correa cascade): chronic infection causes the following changes, which drive progression from normal mucosa to carcinoma:[10][11]
    • Sustained NF-κB-mediated inflammation (IL-1β, IL-6, IL-8, TNF-α)
    • Oxidative and nitrosative DNA damage
    • Aberrant promoter hypermethylation (CDKN2A, MLH1, CDH1)
    • Induction of activation-induced cytidine deaminase, with TP53 mutation
  • Virulence factors: CagA (delivered through the type IV secretion system) and VacA, particularly the s1/m1 genotype, confer substantially higher risk than less virulent strains.[11] CagA also activates the NLRP3 inflammasome, which shapes immune-cell infiltration in gastric cancer.[12]
  • Histologic subtype: H. pylori is associated with both intestinal-type and diffuse-type cancer. Chronic inflammation is not required for diffuse-type carcinogenesis, which implies a distinct mechanism.[1]
  • Causal evidence: a cluster-randomized trial in Linqu County, China, enrolled 180,284 participants with 11.8 years of follow-up. Community-based eradication reduced gastric cancer incidence (intention-to-treat HR 0.86; 95% CI 0.74–0.99). The effect was larger among participants with confirmed eradication (HR 0.81; 95% CI 0.69–0.96).[13][14]

Epstein–Barr virus

  • EBV is associated with approximately 5–10% of gastric cancers.[1][9]
  • EBV-positive tumors have the following features:[1][5]
    • Location in the proximal stomach
    • Occurrence in younger patients
    • Dense immune infiltration with PD-L1/PD-L2 expression
    • Extensive DNA hypermethylation
    • Recurrent PIK3CA, ARID1A, and BCOR mutations

Environmental and Lifestyle Causes

Environmental exposures are believed to drive most non-hereditary cases.[15]

Modifiable environmental and lifestyle risk factors
Exposure Notes
Tobacco smoking Dose- and duration-dependent; independent risk factor; contributes particularly to cardia cancer[9][16]
Heavy alcohol use (≥4 drinks/day) Risk applies at heavy intake[9]
High-salt and salt-preserved foods (salted fish, pickled vegetables, salt-preserved meats) Synergistic with H. pylori[9][14]
Obesity Mainly cardia and GEJ adenocarcinoma[7][14]
GERD and Barrett's esophagus Drives the Western shift toward proximal tumors[7]
Diet low in fruits and vegetables; high in processed or red meat and ultraprocessed foods [15]
  • Other associations: older age, male sex, lower socioeconomic status, poor hygiene, pernicious anemia, and prior gastric ulcer or partial gastrectomy.[1][17]
  • Chronic atrophic gastritis and intestinal metaplasia are intermediate risk states on the causal pathway, not independent exposures.[1]
  • The rising incidence of early-onset gastric cancer (age <50 years) is incompletely explained by known risk factors.[9]

Hereditary and Genetic Causes

  • Hereditary gastric cancer is traditionally divided into three autosomal dominant syndromes:[4]

Hereditary diffuse gastric cancer and CDH1

  • HDGC is an autosomal dominant syndrome of early-onset diffuse gastric cancer and lobular breast cancer. It is caused mainly by inactivating germline CDH1 variants.[18][19]
    • Pathogenic CDH1 variants occur in approximately 1 in 5,000 to 1 in 8,000 people in unselected populations.[19]
  • Mechanism: CDH1 encodes E-cadherin, a transmembrane cell–cell adhesion protein and tumor suppressor.
  • Current penetrance estimates (lower than older pedigree-based figures of approximately 70% in men and 56% in women):[18][19]
    • Cumulative gastric cancer risk to age 80: approximately 37–42% in men and 25–33% in women
    • Lobular breast cancer risk in women: 37–55%
  • Intramucosal foci: nearly all carriers harbor microscopic intramucosal (pT1a) signet ring cell foci. Cancer of any stage is found in 88–97% of risk-reducing gastrectomy specimens, but disease ≥pT1b is found in only about 2–3%. Modeled lifetime risk of advanced (≥stage 2) cancer is approximately 10% in men and 6.5% in women.[19]
  • Other HDGC genes: CTNNA1 (α-E-catenin) accounts for approximately 2% of HDGC families. About 70% of clinically defined HDGC families have no identified causative gene.[3][4]

Other hereditary syndromes

Hereditary syndromes with increased gastric cancer risk
Syndrome Gene(s) Key feature
HDGC CDH1, CTNNA1 Diffuse/signet ring cell gastric cancer; lobular breast cancer
GAPPS APC promoter 1B point variants >100 fundic gland polyps with antral sparing; no colorectal polyposis[4][19]
Lynch syndrome MLH1, MSH2, MSH6, PMS2, EPCAM Intestinal-type, MSI-high tumors
Familial adenomatous polyposis APC Gastric polyps; elevated gastric cancer risk
Li-Fraumeni syndrome TP53 Multiple early-onset cancers
Peutz-Jeghers syndrome STK11 Hamartomatous polyps
Juvenile polyposis syndrome BMPR1A, SMAD4 Gastric juvenile polyps
Cowden syndrome PTEN Hamartomatous polyps
MUTYH-associated polyposis MUTYH Attenuated polyposis
Hereditary breast and ovarian cancer and related BRCA1, BRCA2, PALB2 Modestly increased risk[4][19]

Molecular Etiology

The TCGA classification defines four molecular subtypes with distinct causal mechanisms.[5]

TCGA molecular subtypes of gastric adenocarcinoma
Subtype Approximate frequency Defining features
Chromosomal instability (CIN) ~50% Aneuploidy; frequent TP53 mutation; receptor tyrosine kinase amplification (ERBB2, VEGFA, FGFR2); mostly intestinal type; often at the GEJ
Microsatellite instability (MSI) ~22% Mismatch-repair deficiency, commonly from MLH1 promoter hypermethylation; high tumor mutational burden
Genomically stable (GS) ~20% Diffuse-type histology; CDH1 and RHOA mutations; CLDN18–ARHGAP fusions; peritoneal spread
EBV-positive ~9% Extensive hypermethylation; PIK3CA and ARID1A mutations; PD-L1 overexpression
  • The Asian Cancer Research Group (ACRG) proposed an overlapping classification: MSI, MSS/EMT, MSS/TP53-active, and MSS/TP53-inactive. Its distinct MSS/EMT subtype is marked by CDH1 loss and peritoneal tropism.[22]
  • In routine practice, formal subtype assignment is not yet standard. Only actionable markers are tested: MMR/MSI, HER2, PD-L1, and increasingly EBV and Claudin-18.2.[4][23]
    • Up to about 25% of GEJ tumors fall outside the expected CIN class.[24]

Clinical Implications of Etiology

  • Apply the H. pylori causal link to non-cardia cancer only. Cardia and GEJ cancers are instead linked to obesity, reflux, and Barrett's esophagus.[8][7]
  • A single negative histologic H. pylori test can be falsely negative in atrophic gastritis or intestinal metaplasia; serology captures lifetime infection.[2]
  • Diffuse-type cancer often does not follow the Correa cascade.[1]
  • The following findings should prompt germline CDH1 evaluation per NCCN criteria:[19]
    • Diffuse gastric cancer or T1a signet ring cell carcinoma at any age
    • Diffuse gastric cancer diagnosed before age 50
    • Lobular breast cancer with a personal or family history of diffuse gastric cancer
    • Qualifying family histories

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Sundar R, Nakayama I, Markar SR, Shitara K, van Laarhoven H, Janjigian YY, Smyth EC (June 2025). "Gastric cancer". Lancet. 405 (10494): 2087–2102. doi:10.1016/S0140-6736(25)00052-2. PMID 40319897 Check |pmid= value (help). Vancouver style error: initials (help)
  2. ↑ 2.0 2.1 2.2 2.3 Thrift AP, Wenker TN, El-Serag HB (May 2023). "Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention". Nat Rev Clin Oncol. 20 (5): 338–349. doi:10.1038/s41571-023-00747-0. PMID 36959359 Check |pmid= value (help).
  3. ↑ 3.0 3.1 Decourtye-Espiard L, Guilford P (April 2023). "Hereditary diffuse gastric cancer". Gastroenterology. 164 (5): 719–735. doi:10.1053/j.gastro.2023.01.038. PMID 36740198 Check |pmid= value (help).
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F (August 2020). "Gastric cancer". Lancet. 396 (10251): 635–648. doi:10.1016/S0140-6736(20)31288-5. PMID 32861308 Check |pmid= value (help).
  5. ↑ 5.0 5.1 5.2 Cancer Genome Atlas Research Network (September 2014). "Comprehensive molecular characterization of gastric adenocarcinoma". Nature. 513 (7517): 202–209. doi:10.1038/nature13480. PMC 4170219. PMID 25079317.
  6. ↑ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1994). "Schistosomes, liver flukes and Helicobacter pylori". IARC Monogr Eval Carcinog Risks Hum. 61: 1–241. PMID 7715068.
  7. ↑ 7.0 7.1 7.2 7.3 Hirata Y, Noorani A, Song S, Wang L, Ajani JA (July 2023). "Early stage gastric adenocarcinoma: clinical and molecular landscapes". Nat Rev Clin Oncol. 20 (7): 453–469. doi:10.1038/s41571-023-00767-w. PMC 11869628 Check |pmc= value (help). PMID 37264184 Check |pmid= value (help).
  8. ↑ 8.0 8.1 Nawawi KNM, El-Omar EM, Ali RAR. Screening, surveillance, and prevention of esophageal and gastric cancers. In: Gastrointestinal Oncology. 2nd ed. 2024.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Patel AK, Sethi NS, Park H (February 2026). "Gastric cancer: a review". JAMA. 335 (5): 439–450. doi:10.1001/jama.2025.20034. PMID 41499132 Check |pmid= value (help).
  10. ↑ Liabeuf D, Oshima M, Stange DE, Sigal M (April 2022). "Stem cells, Helicobacter pylori, and mutational landscape: utility of preclinical models to understand carcinogenesis and to direct management of gastric cancer". Gastroenterology. 162 (4): 1067–1087. doi:10.1053/j.gastro.2021.12.252. PMID 34942172 Check |pmid= value (help).
  11. ↑ 11.0 11.1 Tang W, Li F, Zheng H, Zhou S, Li C, Xu X, Fu J (December 2025). "Unveiling hidden players: the role of intratumoral microbiota in gastrointestinal cancer dynamics". J Cancer Res Clin Oncol. 152 (1): 15. doi:10.1007/s00432-025-06401-9. PMC 12715092 Check |pmc= value (help). PMID 41410942 Check |pmid= value (help).
  12. ↑ Wan C, Wang P, Xu Y, Zhu Y, Chen H, Cao X, Gu Y (April 2025). "Mechanism and role of H. pylori CagA-induced NLRP3 inflammasome in gastric cancer immune cell infiltration". Sci Rep. 15 (1): 14335. doi:10.1038/s41598-025-98301-8. PMC 12022178 Check |pmc= value (help). PMID 40274924 Check |pmid= value (help).
  13. ↑ Pan KF, Li WQ, Zhang L, Liu WD, Ma JL, Zhang Y, et al. (November 2024). "Gastric cancer prevention by community eradication of Helicobacter pylori: a cluster-randomized controlled trial". Nat Med. 30 (11): 3250–3260. doi:10.1038/s41591-024-03153-w. PMID 39079993 Check |pmid= value (help).
  14. ↑ 14.0 14.1 14.2 Jayakrishnan T, Ng K (October 2025). "Early-onset gastrointestinal cancers: a review". JAMA. 334 (15): 1373–1385. doi:10.1001/jama.2025.10218. PMID 40674064 Check |pmid= value (help).
  15. ↑ 15.0 15.1 Müller A, He J (March 2023). "A double whammy on gastric cancer risk". N Engl J Med. 388 (13): 1225–1229. doi:10.1056/NEJMe2215503. PMID 36988601 Check |pmid= value (help).
  16. ↑ Zhao G, Liu Y, Wang H, Zhang Y, Shang L, Li L (December 2025). "Global, regional, and national burden of gastric cancer attributable to smoking and a high-sodium diet from 1990 to 2021: a global burden of disease study 2021". BMC Gastroenterol. 26 (1): 52. doi:10.1186/s12876-025-04431-8. PMC 12828996 Check |pmc= value (help). PMID 41340089 Check |pmid= value (help).
  17. ↑ Walter K (June 2026). "Gastric cancer". JAMA. 335 (24): 2176. doi:10.1001/jama.2026.3754. PMID 42166170 Check |pmid= value (help).
  18. ↑ 18.0 18.1 Garcia-Pelaez J, Barbosa-Matos R, Lobo S, Dias A, Garrido L, Castedo S, et al. (January 2023). "Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes". Lancet Oncol. 24 (1): 91–106. doi:10.1016/S1470-2045(22)00643-X. PMC 9810541 Check |pmc= value (help). PMID 36436516 Check |pmid= value (help).
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 19.7 National Comprehensive Cancer Network (2026). "NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, Esophageal, and Gastric (HGAST-1, HGAST-A, HGAST-B)".
  20. ↑ MedlinePlus Genetics, National Library of Medicine. "Hereditary diffuse gastric cancer".
  21. ↑ Graziano F, Humar B, Guilford P (December 2003). "The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice". Ann Oncol. 14 (12): 1705–13. doi:10.1093/annonc/mdg486. PMID 14630673.
  22. ↑ Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. (May 2015). "Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes". Nat Med. 21 (5): 449–456. doi:10.1038/nm.3850. PMID 25894828.
  23. ↑ Röcken C (January 2023). "Predictive biomarkers in gastric cancer". J Cancer Res Clin Oncol. 149 (1): 467–481. doi:10.1007/s00432-022-04408-0. PMC 9889517 Check |pmc= value (help). PMID 36260159 Check |pmid= value (help).
  24. ↑ Walch HS, Borpatragohain R, Jee J, Chatila W, Fong C, Maron SB, et al. (May 2025). "Clinical implications of The Cancer Genome Atlas molecular classification system in esophagogastric cancer". Clin Cancer Res. 31 (10): 1912–1921. doi:10.1158/1078-0432.CCR-24-3473. PMID 40299774 Check |pmid= value (help).

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