Risk Factors and Prevention of Stomach Cancer, Excluding Helicobacter pylori

Age and sex

Like other cancers, the incidence of gastric cancer increases with age; it is also two to three times more common in men than in women [13,14]. In men over 65 years of age, intestinal-type gastric cancer occurs more frequently than the diffuse type, whereas the diffuse type is more common in younger individuals and women [7,15]. According to a 2020 study, cardia gastric cancer occurs approximately four times more frequently in men than in women, with the male-to-female ratio peaking between the ages of 50 years and 69 years. This sex difference in incidence may be due to the protective effect of female hormones against cardia gastric cancer as well as factors such as abdominal obesity (a male-pattern fat distribution) or smoking [16].

Family history and genetics

Having a first-degree relative with gastric cancer is known to increase the risk of gastric cancer by about 2.5 times [17]. Whereas most cases of gastric cancer occur sporadically, about 10% show familial clustering [18]. In high-incidence regions, familial clustering may be due to shared risk factors such as H. pylori infections [19]. In low-incidence areas, genetic factors may play a role, although globally, only 1%–3% of cases are known to be truly hereditary. The three genetic syndromes primarily associated with gastric cancer are hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach, and familial intestinal gastric cancer [18].

HDGC syndrome is caused by cadherin 1 (CDH1) germline mutations, leading to an E-cadherin protein deficiency that results in the development and invasion of signet ring cell carcinoma [20]. For most HDGC patients, the cumulative incidence of gastric cancer by 80 years of age is 70% for men and 56% for women. Women also have a 42% risk of lobular breast cancer [8]. According to the 2015 International Gastric Cancer Linkage Consortium guidelines, CDH1 genetic testing should be performed if any of the following three conditions are met: 1) Families including two or more individuals with gastric cancer at any age, with one confirmed to be diffuse gastric cancer; 2) Individuals diagnosed with diffuse gastric cancer before the age of 40; and 3) Families with individuals diagnosed with both diffuse gastric cancer and lobular breast cancer (one diagnosis before 50 years of age) [21].

Prophylactic total gastrectomy is a potentially life-saving surgery for asymptomatic carriers of the CDH1 mutations. This is because endoscopic surveillance has been reported to be ineffective in HDGC cases, as early HDGC lesions are generally not visible and lie beneath the normal mucosa [22].

According to the 2020 HDGC guidelines, carriers of the CDH1 mutation with a confirmed family history of HDGC should consider prophylactic total gastrectomy, regardless of endoscopic findings. Surgery is typically recommended in early adulthood, between the ages of 20 years and 30 years. For older individuals, prophylactic total gastrectomy is not recommended for patients over 70 years of age, unless there are special circumstances. This is due to the longer recovery periods and increased surgery-related risks in older patients. Those who refuse or wish to delay surgery are advised to undergo annual endoscopic examinations by experienced endoscopists knowledgeable about HDGC; treatment of H. pylori infection is also recommended, if present [23]. A case report from Japan described a patient with HDGC where signet ring cell carcinoma, which had not been visible during endoscopy, was found in seven locations after prophylactic total gastrectomy [24].

Cigarette smoking

Smoking is a significant risk factor for gastric cancer, with studies reporting that cigarette smoke condensate has a carcinogenic effect on the gastric mucosa [25]. Moreover, tobacco products contain more than 70 human carcinogens, including polycyclic aromatic hydrocarbons, nitrosamines, and other N-nitroso compounds [26]. These carcinogens can form covalent bonds with deoxyribonucleic acid (DNA), altering normal DNA function and ultimately leading to the development of gastric cancer [27].

A meta-analysis of 32 research papers published in 2008 showed that current smokers have an increased risk of gastric cancer compared with nonsmokers, including a higher risk of both cardia (relative risk [RR], 1.87; 95% confidence interval [CI], 1.31–2.67) and non-cardia cancer (RR, 1.6; 95% CI, 1.41– 1.8) [28]. Regarding differences in cell differentiation types, a 2002 study reported that both former smokers (adjusted rate ratio, 2.0; 95% CI, 1.1–3.7) and current smokers (adjusted rate ratio, 2.1; 95% CI, 1.2–3.6) had higher risks of intestinal-type gastric cancer than nonsmokers, but there was no association with diffuse-type gastric cancer [29].

According to the Stomach Cancer Pooling Project (StoP Project), published in 2018, current smokers have a higher risk of developing gastric cancer than former smokers. This risk increases with the number of cigarettes smoked per day (≥20 cigarettes per day: odds ratio [OR], 1.32; 95% CI, 1.10–1.58) and the duration of regular smoking (≥40 years: OR, 1.33; 95% CI, 1.14–1.54). The risk of gastric cancer decreased with an increasing number of years since quitting; former smokers who had quit for more than 10 years showed no difference in gastric cancer risk compared with nonsmokers [30].

The most recent meta-analysis, published in 2024, analyzed 205 studies and found that current smokers had a higher probability of developing gastric cancer (RR, 1.53; 95% CI, 1.44– 1.62) compared with never-smokers, whereas former smokers had a somewhat lower risk (RR, 1.3; 95% CI, 1.23–1.37). Current smokers had a higher risk of cardia cancer (RR, 2.08; 95% CI, 1.66–2.61) and of distal cancer (RR, 1.48; 95% CI, 1.33–1.66) compared with non-smokers. The risk of gastric cancer increased with smoking intensity of up to 20 cigarettes per day, with no further increase observed with higher smoking intensities. The risk of gastric cancer increased linearly with the duration of smoking and decreased significantly with increasing time since quitting [31].

Alcohol consumption

Alcohol can promote the absorption and metabolism of carcinogens; form chemical bonds with membrane phospholipids to disrupt tight junction structures; contribute to the regulation of genes related to cancer proliferation, invasion, and metastasis; and generate reactive oxygen species that contribute to the metabolic activation of chemical carcinogens and activate signaling molecules involved in inflammation, metastasis, and angiogenesis. Additionally, alcohol consumption can cause folate deficiency, leading to abnormal DNA methylation, which can contribute to the development of gastric cancer [32].

A 2017 meta-analysis examined the differences in alcoholrelated risk according to the anatomical subtypes of gastric cancer. Heavy alcohol consumption was significantly associated (although the difference was not large [RR, 1.16; 95% CI, 0.98–1.39]) with the risk of non-cardia gastric cancer (RR, 1.19; 95% CI, 1.01–1.40) but not with the risk of cardia gastric cancer [33].

The 2017 StoP Project, which analyzed pooled data from 20 studies (9669 cases and 25336 controls) in Europe, Asia, and North America, found that heavy drinkers (defined as consuming 48–72 g of alcohol per day) had an OR of 1.26 (95% CI, 1.08–1.48) for developing gastric cancer, whereas very heavy drinkers (consuming >72 g per day) had an OR of 1.48 (95% CI, 1.29–1.70). Subgroup analysis revealed that consuming over 48 g of alcohol per day was more strongly associated with the risk of cardia cancer (OR, 1.61; 95% CI, 1.11–2.34) than noncardia cancer (OR, 1.28; 95% CI, 1.13–1.45) and showed a stronger association with intestinal-type gastric cancer (OR, 1.54; 95% CI, 1.20–1.97) than the diffuse type (OR, 1.29; 95% CI, 1.16–2.00). This study also reported that alcohol consumption of <48 g per day did not increase the risk of gastric cancer [34].

A cohort study from 2018 reported no relationship between alcohol consumption and gastric cancer, but suggesting that drinking ≤13–14 g of alcohol per day may have a protective effect against gastric cancer [35].

A meta-analysis of 81 epidemiological studies, published in 2021, reported a consistent association between drinking and gastric cancer, with alcohol consumers having a higher risk of gastric cancer than non-drinkers (OR, 1.2; 95% CI, 1.12–1.27). The risk, according to alcohol consumption, was negligible at 10 g per day (OR, 1.01; 95% CI, 0.94–1.09), slight at 50 g per day (OR, 1.14; 95% CI, 1.06–1.21), and high at 100 g per day (OR, 1.32; 95% CI, 1.18–1.48). When examining gastric cancer by location, cardia gastric cancer (OR, 1.18; 95% CI, 1.03–1.35) showed a stronger association than non-cardia gastric cancer with alcohol consumption (OR, 0.93; 95% CI, 0.76–1.13) [36].

Obesity

The incidence and prevalence of obesity have been increasing in recent years [37]. Obesity-related accumulation of adipose tissue in various organs can lead to abnormal cellular functions, potentially causing chronic diseases such as cancer. Excessive accumulation of abdominal fat is particularly associated with insulin resistance [38]. Since insulin and insulin-like growth factor 1 (IGF-I) play crucial roles in cell proliferation, changes in insulin resistance can lead to impaired apoptosis and tumor development. Additionally, cytokines, such as leptin and adiponectin, produced in response to obesity can cause inflammation and promote cancer development [39,40].

A meta-analysis published in 2009, including data from 10 cohort studies, found that being overweight (body mass index [BMI] ≥25 kg/m²) was associated with an increased risk of gastric cancer in non-Asians (OR, 1.24; 95% CI, 1.14–1.36) but not in Asians (OR, 1.17; 95% CI, 0.88–1.56) [41]. A meta-analysis of 24 prospective studies published before 2012 showed that being overweight (BMI, 25–29.9 kg/m²) or obese (BMI ≥30 kg/m²) was not associated with gastric cancer, overall. However, when gastric cancer was classified according to location, obesity was associated with an increased risk of cardia cancer. The summary relative risk (SRR) for cardia cancer was 1.21 (95% CI, 1.03–1.42) for overweight individuals and 1.82 (95% CI, 1.32–2.49) for obese individuals; there was no association with non-cardia cancer risk (overweight SRR, 0.93; 95% CI, 0.82–1.05 and obese SRR, 1.00; 95% CI, 0.87–1.15) [42].

A 2022 study (n=538835) published by the Asian Cohort Consortium examined the association between BMI and gastric cancer in 8997 gastric cancer patients and, contrary to previous studies, found that both underweight and obesity were associated (a U-shaped association) with gastric cancer risk compared with the normal BMI group (hazard ratio [HR], 1.15; 95% CI, 1.05–1.25 and HR, 1.12; 95% CI, 1.03–1.22, for underweight and obese individuals, respectively). Subtype analysis revealed that being underweight or obese was associated with non-cardia, intestinal-type gastric cancer, and cancer occurring in those over 70 years old. However, this study was limited by its focus on Asian populations, with fewer overweight or obese individuals with predominantly non-cardia cancers, making it difficult to confirm the association between obesity and cardia cancer [43].

A meta-analysis of the association between weight and gastric cancer, published in 2023, included 14020031 participants from 13 studies. The pooled RR for gastric cancer was 1.124 (95% CI, 0.968–1.304; heterogeneity statistic [I²], 89.08%) in the underweight group, 1.155 (95% CI, 1.051–1.270; I², 95.18%) in the overweight group, and 1.218 (95% CI, 1.070–1.386; I², 97.65%) in the obese group, indicating that being overweight or obese increased the risk of gastric cancer. Subgroup analysis showed that the association between being overweight/obese and gastric cancer was stronger in non-Asians and women than in Asians and men, with no significant difference between cardia and non-cardia cancers. The relatively minor role of BMI as a risk factor for gastric cancer among Asians may be attributed to other factors, such as H. pylori infection, genetic factors, high-sodium diets, and other environmental factors that play more prominent roles in gastric cancer development in this population [38].

High-salt diet

High salt intake has been reported to increase H. pylori colonization, exacerbate gastritis, and potentially accelerate H. pylori-associated carcinogenesis [44]. Furthermore, excessive salt consumption can damage the gastric mucosa and promote gastric cancer development by increasing DNA synthesis and cell proliferation [45].

A meta-analysis of data from seven cohort studies in 2012 showed that a high-salt diet increases the risk of gastric cancer compared with a low-salt diet (RR, 1.6; 95% CI, 1.41–1.8) [46]. A 2015 study on the relationship between dietary factors and gastric cancer reported that increasing salt intake by 5 g per day was associated with a 12% increase in gastric cancer risk [47].

A meta-analysis of data from 25 case-control studies in the 2022 StoP Project revealed that individuals who prefer salty foods have a higher risk of gastric cancer compared with those preferring tasteless foods (OR, 1.59; 95% CI, 1.25–2.03). Individuals in the highest tertile of the highly salted food consumption group also had a higher risk of gastric cancer (OR, 1.24; 95% CI, 1.01–1.51) than those in the lowest tertile. These associations were consistently observed regardless of H. pylori infection status [48].

Another meta-analysis in 2022, which included 38 case-control studies, demonstrated a significant association between high salt intake and gastric cancer (OR, 1.55; 95% CI, 1.45–1.64; p<0.001) [49].

Fruit and vegetable consumption

Fruits and vegetables are rich in antioxidants and anticancer substances, such as vitamin C, carotenoids, and catechins. These antioxidant properties can potentially eliminate free radicals that may cause mutations, induce the production of detoxifying enzymes, and counteract DNA damage caused by H. pylori [50-52].

According to a meta-analysis published in 2007, high consumption of fruits and vegetables is associated with a reduced risk of gastric cancer, with a pronounced association with intestinal-type gastric cancer [53]. A 2014 meta-analysis study that included over 2.4 million individuals (6600 gastric cancer patients) followed for more than 10 years showed that fruit consumption was associated with gastric cancer risk reduction (SRR, 0.9; 95% CI, 0.83–0.98). However, this study found that vegetable consumption did not reduce the risk (SRR, 0.96; 95% CI, 0.88–1.06) [54].

The meta-analysis results from the StoP Project published in 2020 reported data showing that people in the highest tertile of fruit consumption (OR, 0.76; 95% CI, 0.64–0.90), vegetable consumption (OR, 0.68; 95% CI, 0.56–0.84), and combined fruit and vegetable intake (OR, 0.61; 95% CI, 0.49–0.75) had significantly reduced risks of gastric cancer development compared with those in the lowest tertile [55].

A 2023 meta-analysis study reported that total fruit intake (RR, 0.87; 95% CI, 0.8–0.94) and total fruit and vegetable intake (RR, 0.75; 95% CI, 0.61–0.93) were associated with a 13% and 25% lower risk of gastric cancer, respectively. The study also found that for every 100 g increase in daily total fruit intake (pooled RR, 0.95; 95% CI, 0.90–0.99) and every 200 g increase in daily total fruit and vegetable intake (pooled RR, 0.94; 95% CI, 0.88–0.99), the risk of gastric cancer was reduced by 5% and 6%, respectively [56].

Other dietary factors

Meta-analyses have been conducted on various dietary factors, in addition to fruits and vegetables. Notably, the ongoing StoP Project (established in 2012) investigating lifestyle, environmental, and genetic determinants of gastric cancer [57] has been sequentially publishing research results. Recent studies have identified excessive alcohol consumption, total meat intake, red meat, processed meat, and salt intake, as risk factors for gastric cancer. In contrast, fruits, vegetables, mushrooms, green tea, polyphenol, and vitamin C intake have been shown to reduce the risk [58,59].

Nonsteroidal anti-inflammatory drugs

Aspirin is known to reduce the risk of colorectal, breast, and lung cancers, and several studies have reported its effects on gastric cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, can have antitumor growth effects through cyclooxygenase-2 (COX-2) blockade, inhibition of angiogenesis, and upregulation of mediators (such as caspase-3 activation) that induce apoptosis [12]. Additionally, aspirin and nonaspirin NSAIDs can exert chemopreventive effects through COX-independent pathways, including nuclear factor-κB, activated protein 1, Wnt-β-catenin, and extracellular signal-regulated kinase [12].

A 2009 cohort study in the United States, involving 643 cancer patients and 168649 cancer-free individuals, found that regular aspirin use was associated with a reduced risk of distal gastric cancer (HR, 0.73; 95% CI, 0.61–0.89; p_trend=0.009). However, the use of non-aspirin NSAIDs was not associated with a reduced risk of distal gastric cancer (HR, 1.00; 95% CI, 0.81– 1.24; p_trend=0.99). The inverse relationship between regular aspirin use and gastric cancer development was observed only in intestinal-type distal gastric adenocarcinoma (HR, 0.66; 95% CI, 0.47–0.95; p_trend=0.01) and not in diffuse-type distal gastric adenocarcinoma (HR, 0.92; 95% CI, 0.53–1.60; p_trend=0.45) [60].

A 2017 study showed that NSAIDs reduced the risk of gastric cancer for all types of NSAIDs (RR, 0.78; 95% CI, 0.72– 0.85), aspirin (RR, 0.70; 95% CI, 0.62–0.80), and for non-aspirin NSAIDs (RR, 0.86; 95% CI, 0.80–0.94), with particular effectiveness for reducing the risk of non-cardia gastric cancer. A dose-response analysis showed that for every 2-year increase in the duration of NSAID and aspirin use, the risk of gastric cancer decreased by 11% and 5%, respectively [61].

A 2020 meta-analysis of the association between aspirin use and gastric cancer used fixed- and random-effects models; the pooled risk ratios for gastric cancer incidence were 0.890 (95% CI, 0.871–0.909) and 0.826 (95% CI, 0.740–0.922), respectively, indicating an association with reduced gastric cancer occurrence. Preventive effects were observed after weekly or daily aspirin use rather than with intermittent or monthly use. A subgroup analysis described the preventive effects of aspirin use within 5 years and its effectiveness in reducing non-cardia gastric cancer [62].

Another 2020 meta-analysis analyzed the effect of aspirin in reducing the risk of gastric cancer. Low-dose aspirin showed slightly greater risk reduction (OR, 0.80; 95% CI, 0.59–1.09) than high-dose aspirin (OR, 1.08; 95% CI, 0.77–1.52). The protective effect associated with aspirin use for more than five years (OR, 0.67; 95% CI, 0.34–1.31) was greater than that for aspirin use for less than 5 years (OR, 1.01; 95% CI, 0.72–1.43), suggesting that low-dose aspirin use for more than five years could reduce gastric cancer risk [63].

To date, the reported risk-reduction effects of NSAIDs on gastric cancer have generally shown better results for aspirin than for other NSAIDs, with long-term use showing risk-reduction effects associated with non-cardia gastric cancer. However, well-designed randomized controlled trials are lacking, and the type, dosage, duration, and frequency of drug use have not been clearly defined. Moreover, the risk of side effects (e.g., bleeding) associated with the use of these drugs must be considered. Therefore, recommending aspirin use for the prevention of gastric cancer is currently difficult.

Statins

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, a class of drugs that lowers serum lipid levels. Various metabolites of cholesterol metabolism are involved in the carcinogenesis process [64]. The inhibition of HMG-CoA reductase leads to a decrease in mevalonic acid, which downregulates mediators essential for the downstream regulation of G-protein-coupled receptors in various pathways, notably the Ras signaling pathway that promotes cell growth and survival in various cancer cells. Statins are also described as having antiangiogenic, antiproliferative, and proapoptotic effects, and are known to inhibit the growth of several tumor types, including gastric cancer, in vitro and in animal models [64,65].

A 2013 meta-analysis found an association between statin use and a reduced risk of gastric cancer (adjusted OR, 0.84; 95% CI, 0.78–0.90). This association was observed in both Asian (adjusted OR, 0.68; 95% CI, 0.53–0.87) and Western populations (adjusted OR, 0.86; 95% CI, 0.79–0.93). Long-term (≥2 years) statin use (OR, 0.35; 95% CI, 0.16–0.76) showed an increased protective effect against gastric cancer compared with short-term use (<2 years; OR, 0.73; 95% CI, 0.51–1.05) [66].

A 2013 meta-analysis of data from 26 randomized controlled trials showed that statin use is associated with a 27% reduction in gastric cancer risk (RR, 0.73; 95% CI, 0.58–0.93). However, this protective effect decreased, but remained significant, when studies focusing solely on patients with diabetes were excluded (RR, 0.85; 95% CI, 0.80–0.91) [67].

A 2021 retrospective study in Korea showed that statins reduced the risk of metachronous gastric cancer after endoscopic resection of early gastric cancer [68].

A 2022 meta-analysis of 20 case-control and randomized controlled studies found that statin use was associated with a reduction in gastric cancer risk (adjusted RR, 0.72; 95% CI, 0.64–0.81; p<0.001). When analyzed by patient ethnicity, the effect of statin use on gastric cancer risk showed a more protective effect in Asians than in Westerners (Asian RR, 0.62; 95% CI, 0.53–0.73 vs. Western RR, 0.88; 95% CI, 0.79–0.99) [69].

A meta-analysis published in 2023, analyzing 23 studies, found that patients in the statin use group had a significantly lower risk of gastric cancer than those in the non-statin use group (OR/RR, 0.74; 95% CI, 0.67–0.80; p<0.001). The study also showed that the statin use group had significantly lower all-cause mortality and gastric cancer-specific mortality than the non-statin use group (all-cause mortality: RR, 0.70; 95% CI, 0.52–0.95; p=0.021; cancer-specific mortality: RR, 0.70; 95% CI, 0.58–0.84; p<0.001) [70].

Metformin

Diabetes is a known risk factor for gastric cancer [71]. The anticancer effect of metformin, which is primarily used in the treatment of diabetes, is mediated through various pathways. Metformin acts as an insulin sensitizer, reducing the production of insulin and IGF. This can inhibit the IGF signaling pathway that promotes the proliferation of cancer cells expressing IGF receptors [72]. Secondly, the activation of adenosine monophosphate-activated protein kinase and the subsequent inhibition of the mammalian target of rapamycin complex 1 signaling pathway and survivin (a protein that inhibits cancer cell apoptosis) are known to induce cancer cell death [73-76].

Several clinical studies have reported an association between metformin use and gastric cancer. In a 2014 study by Kim et al. [77], patients who did not use insulin but who used metformin for more than 3 years showed a 43% reduction in gastric cancer risk, whereas there was no difference in gastric cancer incidences between patients using or not using metformin among individuals using insulin. In 2016, Lee et al. [78] reported that among gastrectomy patients with diabetes, the use of metformin for more than 6 months reduced cancer-related mortality and recurrence rates. A 2017 meta-analysis showed that metformin treatment in patients with type 2 diabetes lowered the risk of gastric cancer development (HR, 0.763; 95% CI, 0.642– 0.905) [79]. A 2019 study from Taiwan reported that metformin use in patients with diabetes, after H. pylori eradication, demonstrated a reduced risk (reduction of approximately 51%) of gastric cancer, with a trend related to dose and duration of use [80]. A meta-analysis published in 2020 analyzed 11 cohort studies and reported that metformin use reduced gastric cancer incidence by 21% in patients with type 2 diabetes. However, this effect, observed in Asians, was not observed in Western patients [81].

A 2023 study analyzing the cancer prevention effects of metformin on various cancer types showed that metformin reduced the incidence of liver, pancreatic, colorectal, and gastric cancers (OR, 0.72; 95% CI, 0.26–1.99) [82]. Although numerous studies have reported the preventive effect of metformin on gastric cancer, there have also been studies showing no effect [83-86]. Additionally, as most of these are observational studies, the results may be biased due to unadjusted confounding factors [87].