Risk for gastric adenocarcinoma (>90% of stomach cancers) is dominated by chronic Helicobacter pylori infection. H. pylori is an IARC Group 1 carcinogen and is associated with roughly 90% of non-cardia (gastric body and antrum) cancers.^[1][2] It drives the stepwise Correa cascade: chronic gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → carcinoma.^[3][4]

Other modifiable risk factors are tobacco smoking, heavy alcohol use, high dietary salt and salt-preserved foods, processed meat, and obesity. Nonmodifiable factors include older age, male sex, high-risk ancestry or immigration from high-incidence regions, prior partial gastrectomy, prior abdominal radiotherapy, autoimmune gastritis/pernicious anemia, and inherited predisposition. The most important inherited cause is a germline CDH1 pathogenic variant causing hereditary diffuse gastric cancer (HDGC).^[2]

Risk-factor profiles differ by anatomic site and histology:

• Non-cardia, intestinal-type cancer is overwhelmingly H. pylori–driven and arises from precancerous mucosal lesions.
• Cardia/gastroesophageal junction (GEJ) cancer is more closely linked to obesity and gastroesophageal reflux disease (GERD).^[4]
• Diffuse-type cancer can arise without a precursor inflammatory field. This includes the hereditary (CDH1) form.^[5]

• H. pylori has been classified as a Group 1 (definite) carcinogen since 1994. It is the single most important gastric cancer risk factor worldwide.^[1][4]
• Using sensitive immunoblot-based serology, the worldwide attributable fraction for non-cardia gastric cancer is ~89%. Infection is associated with both intestinal- and diffuse-type disease.^[6][7]
• The attributable fraction varies by region and anatomic site:
  • Non-cardia cancer: OR 4.36 in East Asia and 4.03 in the West. H. pylori accounts for an estimated 71.2% of non-cardia cancer in East Asia and 73.2% in the West.^[8]
  • Cardia cancer: a significant association exists only in East Asia (OR 2.86, ~61% attributable), not in Western populations (OR 0.80).^[8]
  • Across 27 countries, more than two-thirds of new gastric cancers in 2022 were attributable to H. pylori. The attributable fraction exceeded 70% in Africa, the Eastern Mediterranean, most of Latin America, China, Japan, and Korea.^[9]
  • Of 15.6 million lifetime gastric cancers projected for people born in 2008–2017, ~76% are attributable to H. pylori.^[10]
• Only a minority of infected people develop cancer: about 3% lifetime, while ~17% develop some precancerous progression. Cancer development depends on co-factors such as oxyntic atrophy, strain virulence, and host and environmental exposures.^[3]
• Strain virulence matters. cagA-positive strains (especially the East Asian EPIYA-D motif) and certain vacA genotypes confer higher non-cardia cancer risk.^[4][3]
• Eradication reduces incidence:
  • In a community cluster-randomized trial (Linqu County, China; 180,284 participants; 11.8 years of follow-up), treatment reduced gastric cancer incidence (HR 0.86; 95% CI 0.74–0.99).
  • The effect was stronger with confirmed eradication (HR 0.81; 95% CI 0.69–0.96).^[11]
  • In patients with gastric intestinal metaplasia, the American Gastroenterological Association (AGA) recommends testing for and eradicating H. pylori (strong recommendation, moderate-quality evidence).^[12]

• EBV-associated gastric carcinoma accounts for ~8–10% of gastric cancers worldwide. It is a distinct TCGA molecular subtype.^[2][13]
• Clinical phenotype: more often proximal (cardia/corpus), more common in men, with prominent lymphocytic infiltration.
• Molecular features: extensive CpG island hypermethylation (e.g., CDKN2A/p16 promoter silencing), frequent PIK3CA mutation, and PD-L1/PD-L2 overexpression.^[5][14]
• A 2025 two-sample Mendelian randomization study found that genetically predicted EBNA-1 antibody levels were associated with gastric cancer (MR-PRESSO OR 1.23; 95% CI 1.05–1.44). This supports a causal contribution.^[15] However, IARC has historically regarded direct causal evidence for gastric cancer as limited.

Atrophic gastritis is defined histologically by loss of gastric glands, usually from chronic H. pylori injury or autoimmunity. The presence of intestinal metaplasia almost always implies atrophy.^[16] Risk rises with lesion severity, histologic subtype, and anatomic extent:

• Corpus-involving or extensive disease carries higher risk than antrum-limited disease.
• Incomplete intestinal metaplasia carries higher risk than complete intestinal metaplasia.
• Risk stratification tools include OLGA/OLGIM histologic staging and the endoscopic Kimura–Takemoto classification (open-type atrophy predicts progression).^[17]

• Autoimmune gastritis causes corpus-predominant autoimmune destruction of oxyntic mucosa. The result is achlorhydria, hypergastrinemia, and enterochromaffin-like cell (ECL-cell) hyperplasia. It is a major cause of atrophic gastritis where H. pylori prevalence is low.^[16]
• Pernicious anemia confers an approximately 7-fold increase in gastric adenocarcinoma risk (most individual studies report 2- to 4-fold). It also predisposes to type 1 gastric neuroendocrine tumors (~0.4–0.7% per year).^[16]

• Tobacco smoking: independent, dose-dependent risk factor (pooled OR ~1.25). About 17–18% of cases are attributable to smoking, and the effect on cardia cancer is stronger.^[2][21][22]
• Heavy alcohol use (≥4 drinks/day): pooled OR ~1.37 vs never-drinkers.^[2][7]
• High salt and salt-preserved or smoked foods (salted fish, pickled vegetables, cured meats): salty-taste preference carries an OR of ~1.59.^[2][23]
  • The effect is amplified in H. pylori–infected individuals.^[24]
• Red and processed meat: consistently associated with increased non-cardia risk.^[24][25]
• Obesity: associated mainly with cardia/GEJ adenocarcinoma through the reflux pathway. The association with non-cardia cancer is inconsistent.^[4][26]
• GERD and Barrett esophagus: risk factors for cardia/GEJ adenocarcinoma.^[3][4]
• Protective factors: diets rich in fresh fruit, vegetables, and fiber. Part of this effect may come from reduced intragastric N-nitroso compound formation.^[27][28]

• Age and sex: >80% of cases are diagnosed at age ≥55 (median 68 years), and incidence in men is roughly twice that in women.^[2] Incidence in people younger than 50 is rising, especially among women.^[2][29]
• Race/ethnicity, immigration, and socioeconomic status: risk is higher in first-generation immigrants from high-incidence regions and in several non-White racial and ethnic groups, including East Asian, Latino, and Eastern European populations. These groups form the basis for targeted screening in low-incidence countries.^[27]
• Prior gastric surgery: risk is increased in the gastric remnant years after distal gastrectomy, attributed to bile and pancreatic juice reflux. Risk is higher after Billroth II than Billroth I reconstruction.^[30]
• Prior radiotherapy: risk is elevated in survivors of Hodgkin lymphoma, testicular cancer, and childhood cancers treated with abdominal radiation.^[31]
• ABO blood group A: incidence ratio ~1.2 vs group O; clinically minor.^[32]

About 10% of gastric cancers show familial aggregation, but defined heritable syndromes account for only ~1–3% of the global burden.^[3][33]

• Definition and genetics:
  • HDGC is an autosomal dominant syndrome of early-onset diffuse (signet-ring cell) gastric cancer and lobular breast cancer.
  • It is caused by germline CDH1 (E-cadherin) pathogenic variants and, less commonly, CTNNA1 (α-catenin) variants.^[34][35]
• Penetrance has been revised downward:
  • Early estimates from families meeting strict clinical criteria placed cumulative gastric cancer risk by age 80 at 70% in men and 56% in women, with a 42% breast cancer risk in women.^[35]
  • In carriers not selected exclusively by clinical criteria, cumulative gastric cancer risk by age 80 was 42% in men and 33% in women, and breast cancer risk was 55%. Earlier estimates were judged inflated by ascertainment bias.^[36]
  • In 213 North American families with CDH1 pathogenic/likely pathogenic variants, cumulative risk of advanced gastric cancer by age 80 was 10.3% in male and 6.5% in female carriers. Breast cancer risk in female carriers was 37%.^[37]
  • Genotype-first data confirm that CDH1 pathogenic and likely pathogenic variants are associated with diffuse gastric and lobular breast cancer. CDH1 missense variants of uncertain significance showed no such association.^[38]
• Natural history: multifocal intramucosal (pT1a) signet-ring cell carcinoma foci are found in >95% of carriers. The incomplete penetrance of advanced disease likely reflects failure of most pT1a foci to progress.^[39]
• Risk reduction: prophylactic total gastrectomy remains the definitive risk-reducing intervention for CDH1/CTNNA1 carriers.^[40][34]
  • Endoscopic surveillance with systematic random biopsies at an expert center is an option for carriers who defer or decline surgery.
  • In a 16-year prospective cohort, omitting random (non-targeted) biopsies would have missed 42% of signet-ring cell carcinoma diagnoses.^[41]

• CDH1 carriers — gastrectomy vs surveillance: guidelines still favor risk-reducing total gastrectomy. Lower penetrance estimates and surveillance data have reopened whether selected carriers can be managed endoscopically. Biopsy sensitivity for superficial signet-ring cell carcinoma remains suboptimal.^[37][41][39]
• Committed precancerous state: it is debated whether atrophy and intestinal metaplasia without ongoing H. pylori infection represent a committed precancerous state. The relative contribution of pyloric metaplasia, and its evolution into incomplete intestinal metaplasia, is also being clarified.^[17][45]
• Atrophy in low-incidence populations: the evidence base for atrophy-specific surveillance is heterogeneous. Many studies fail to separate atrophy from intestinal metaplasia or autoimmune from H. pylori–associated atrophy.^[19] Progression rates of atrophic gastritis are lower in low-incidence countries.^[18]
• Obesity and non-cardia cancer: the association is inconsistent; the effect is clearer for cardia/GEJ disease.^[24]
• EBV: its direct causal weight, as opposed to a co-factor role with H. pylori, is still being clarified.^[15]
• Population screen-and-treat programs: cost-effectiveness and optimal target populations for population-wide H. pylori screen-and-treat in low-incidence regions remain under study.^[10]

• Test for and treat H. pylori in patients with gastric intestinal metaplasia or prior gastric neoplasia and in those with a first-degree family history of gastric cancer.^[12][3]
• Stratify precancerous lesions by subtype and extent. Incomplete or extensive intestinal metaplasia, OLGA/OLGIM stage III–IV, and any dysplasia identify patients who may benefit from endoscopic surveillance.^[12][17]
• Consider targeted endoscopic screening in high-risk groups in low-incidence countries: first-generation immigrants from high-incidence regions, certain non-White racial and ethnic groups, first-degree family history, and hereditary syndromes. Details are in the Screening microchapter.^[27]
• Refer for germline genetic testing according to NCCN criteria. Examples include diffuse gastric cancer or pT1a signet-ring cell carcinoma at any age, gastric cancer diagnosed before age 50, and lobular breast cancer with a personal or family history of diffuse gastric cancer.^[46]
• Counsel patients on modifiable factors: smoking cessation, limiting alcohol, reducing salt, salt-preserved, and processed-meat intake, increasing fruit and vegetable intake, and weight management (particularly for cardia/GEJ risk).^[27]

• Treating all intestinal metaplasia as equal risk, without stratifying by subtype, extent, or OLGIM stage.
• Attributing diffuse-type cancer to H. pylori/atrophy alone and missing a hereditary (CDH1) or EBV etiology, especially in young patients or those with a family history of lobular breast cancer.
• Relying on a negative histology or urea breath test to exclude prior H. pylori infection when atrophy is extensive, because the organism may be cleared as atrophy advances. Serology reflects past exposure.^[9]
• Counseling CDH1 carriers with the historical ~70% lifetime gastric cancer figure, which overstates risk relative to current estimates.^[36][37]