Gastric cancer is a significant global health challenge, representing the fifth most common malignancy and third leading cause of cancer-related deaths worldwide [1]. The prognosis of patients with gastric cancer remains poor, with survival rates that have not improved substantially over the last few decades, mainly because of late-stage diagnoses and limited screening tools. This underscores the need for preventive strategies to reduce the risk factors associated with this disease.

Among the various risk factors for gastric cancer, Helicobacter pylori infection has been identified as a principal contributing factor. H. pylori is recognized as a class I carcinogen by the World Health Organization, with approximately half of the world’s population being infected and with incidence rates varying significantly across different geographic and socioeconomic groups [2]. The relationship between H. pylori and the sequential development of gastric cancer is well documented and involves the Correa cascade that begins with chronic gastritis and leads to atrophic gastritis, intestinal metaplasia, dysplasia, and ultimately carcinoma [3]. The concept of H. pylori eradication as a preventive strategy against gastric cancer has gained considerable attention, and substantial evidence suggests that such eradication therapy would significantly reduce the incidence of gastric cancer [4].

This review summarizes the epidemiology of H. pylori infection and gastric cancer, pathophysiology and mechanisms of H. pylori-induced gastric cancer, and impact of H. pylori eradication therapy on prevention of gastric cancer.

The association between H. pylori infection and the incidence of gastric cancer is particularly evident in Asian countries, including Korea and Japan. A prospective study conducted in Japan demonstrated a direct association between the risk of developing gastric cancer and the presence of H. pylori infection, with significant reduction in the incidence of gastric cancer following H. pylori eradication [5]. The incidence of H. pylori infection varies by geographic region, and its prevalence is higher in developing countries than in developed ones owing to factors such as socioeconomic status, sanitation levels, and living conditions [6,7]. However, in many regions, the prevalence of H. pylori infection has been declining, as sanitation and living standards have improved.

Although many H. pylori-infected patients are asymptomatic, once infected, H. pylori infections generally persist for the duration of the patient’s life, leading to various symptoms via a combination of bacterial, host, and environmental factors. Ultimately, gastric ulcers and gastric adenocarcinoma occur in 10%–15% and 1%–3% of infected patients, respectively [8,9]. A prospective study conducted in Korea and Japan demonstrated a direct association between the risk of developing gastric cancer and the presence of H. pylori infection and stated that H. pylori eradication therapy can reduce the risk of gastric cancer [5,10].

Recognized as a primary risk factor for gastric cancer, H. pylori infection initiates pathological changes ranging from atrophic gastritis to intestinal metaplasia and dysplasia. The role of H. pylori in non-cardia gastric cancer is well established; however, its involvement in cardia gastric cancer remains unclear. A large-scale study involving more than 500000 Chinese patients revealed that H. pylori infections were responsible for a significant percentage of non-cardia (78.5%) and cardia (62.1%) gastric cancers [11]. Another Chinese meta-analysis showed a correlation between H. pylori infection and non-cardia gastric cancer in East Asia (odds ratio [OR]=4.36, 95% confidence interval [CI]=3.54–5.37) and the West (OR=4.03, 95% CI=2.59– 6.27). However, for cardia gastric cancer, a significant association was observed only in East Asia (OR=2.86, 95% CI=2.26– 3.63), with no similar association found in the West (OR=0.80, 95% CI=0.61–1.05) [12]. These results suggest an association between H. pylori infection and gastric cancer, including an association with the regional differences in the incidence of cardia cancer.

H. pylori is implicated in approximately 90% of gastric carcinomas, representing the predominant etiological factor in infection-related malignancies and accounting for 5.5% of the global cancer burden [13,14]. Most H. pylori infection-related gastric cancers manifest as gastric adenocarcinomas and are histologically classified into two types: intestinal or diffuse cancers. H. pylori is more commonly associated with intestinal adenocarcinomas, which typically present with corpus-dominant gastritis, gastric atrophy, and intestinal metaplasia. In contrast, diffuse adenocarcinomas exhibit gastritis without atrophy or metaplasia [15]. The oncogenic mechanisms through which H. pylori promotes the development of gastric cancer are complex and influenced by various virulence, host genetic, and environmental factors. The morphology of H. pylori, particularly its spiral shape and flagella, enhances its motility, enabling it to navigate the mucosal layer and reach the gastric epithelium. Its surface adhesins facilitate adherence to gastric epithelial cells, while the enzyme urease converts urea to ammonia, buffering the gastric acid and promoting mucosal penetration and epithelial damage. H. pylori also produces catalase, which detoxifies reactive oxygen species generated during inflammation [16,17].

Among the bacterial factors implicated in the pathogenesis of H. pylori infection, the cytotoxin-associated gene A protein (CagA) is notably translocated into gastric epithelial cells via the bacterial type IV secretion system. This process results in a cascade of immune responses and contributes to the development of gastroduodenal diseases, such as peptic ulcer and gastric cancer. In a study involving Mongolian gerbils, infection with a CagA-positive strain of H. pylori was shown to induce gastric cancer, whereas an isogenic mutant strain lacking CagA did not [18]. Additionally, transgenic mice engineered to express cagA were reported to develop gastric cancer [19]. A meta-analysis of 16 studies evaluating the relationship between CagA and gastric cancer showed that CagA seropositivity increased the risk for non-cardia gastric cancer (OR=2.01, 95% CI=1.21–3.32). These results suggest that patients infected with CagA-positive H. pylori strains are at a greater risk of developing gastric cancer than those infected with CagA-negative strains [20].

Vacuolating cytotoxin A (VacA) is another important virulence factor that functions as an intracellular-acting protein exotoxin with a major target site on the host mitochondrial inner membrane. However, vacuolating activity varies across different H. pylori strains, predominantly due to polymorphisms in vacA at the signal (s)-region (s1 and s2) and the middle (m)-region (m1 and m2) [19,21]. Numerous studies have reported that individuals infected with the s1 or m1 H. pylori strains have a higher risk of developing peptic ulcer disease or gastric cancer than those infected with the s2 or m2 strains [21,22].

Besides these virulence factors, host factors, such as host cytokine gene polymorphisms, have been associated with increased non-cardia gastric adenocarcinoma [23].

For several decades, researchers globally have investigated the influence of H. pylori eradication on the risk of gastric cancer and the evolution of premalignant gastric conditions. In 1994, the International Agency for Research on Cancer of the World Health Organization classified H. pylori as a class I carcinogen, based on previous epidemiological data [24-26]. Several systematic reviews and meta-analyses, including randomized control trials (RTCs), have reported that H. pylori eradication can decrease the risk of developing gastric cancer by approximately 34%–40% in asymptomatic patients and by 54% in patients with gastric cancer by preventing recurrence after endoscopic resection [27,28]. An RCT involving 3365 participants from a nutritionally deprived population showed that short-term treatment with amoxicillin and omeprazole reduced the incidence of gastric cancer by 39% over 15 years following randomization [29].

However, the benefit of treating H. pylori in populations with different levels of gastric cancer risk (in terms of asymptomatic patients, atrophic gastritis, intestinal metaplasia, and history of endoscopic resection for gastric cancer) remains unclear. A systematic review and meta-analysis of RCTs and observational studies assessed the treatment of H. pylori in different clinical scenarios [4] and showed that the protective effect of H. pylori eradication was greater in patients with higher baseline gastric cancer risks. In that study, the authors identified 24 eligible studies (22 from Asia) involving 715 incidents of gastric cancer among 48000 individuals, with 340000 person-years of follow-up. Individuals who received H. pylori eradication therapy had a lower incidence of gastric cancer (pooled incidence rate ratio=0.53, 95% CI=0.44–0.64). In addition, eradication treatment was associated with a substantially lower gastric cancer risk in individuals who had asymptomatic infections (pooled incidence rate ratio=0.62, 95% CI=0.49–0.79) and in individuals who had undergone endoscopic gastric cancer resection (pooled incidence rate ratio=0.46, 95% CI=0.35–0.60) [4].

In a study from Hong Kong, treatment of H. pylori infection lowered the risk of gastric cancer, particularly in persons aged >40 years, 10 or more years after treatment [30]. In addition, high-risk operative link for gastritis assessment (OLGA) and operative link for gastric intestinal metaplasia (OLGIM) stages were found less frequently in individuals aged <40 years; therefore, H. pylori treatment prior to age of 40 years may be effective in decreasing the risk of developing gastric cancer [31]. A Korean study showed that H. pylori eradication therapy can reduce the risk of gastric cancer in populations with a family history of gastric cancer. Specifically, gastric cancer developed in 0.8% of patients after H. pylori eradication therapy but in 2.9% of patients with persistent infection [10]. Table 1 shows the key studies regarding the cancer-prevention effects of H. pylori eradication therapy, as reported in a recent meta-analsysis [28].

However, most of these studies were conducted in Asia and parts of the world where gastric cancer is more common. Therefore, whether non-selective H. pylori eradication affects the baseline risk of gastric cancer remains unclear. Similarly, whether interactions between host genetic factors and bacterial virulence factors, which can vary across populations, can result in different levels of gastric cancer risk also remains unclear [4]. Additionally, whether H. pylori eradication can reverse the gastric mucosal damage associated with atrophic gastritis and/or intestinal metaplasia is also unclear. Some studies have reported that these precursor lesions can improve after eradication. However, other studies have found that eradication does not lead to significant changes. Several previous studies have shown that eradication in H. pylori carriers without premalignant gastric lesions significantly decreased the development of gastric cancer but did not decrease the development in patients with atrophic gastritis and/or intestinal metaplasia [32,33]. Based on these results, many researchers have suggested a “point of no return” theory; however, opposite results have been recently reported.

The effectiveness of mass H. pylori eradication in Asian populations showed that gastric cancers occurred less frequently among persons who underwent eradication therapy (3294 cases, 1.6%) compared with that in control individuals (3203 cases, 2.4%) [27]. Other studies showed that H. pylori infection could reduce gastric atrophy, but intestinal metaplasia remained unchanged, despite successful eradication [34,35]. Other studies have shown that H. pylori eradication did not decrease the incidence of gastric cancer, especially in patients with intestinal metaplasia or dysplasia, which did not improve following H. pylori eradication and that eradication therapy did not improve miRNA dysregulation in the intestinal metaplastic glands or gastric mucosa of patients in a high-risk group for gastric cancer [36-38]. However, even though eradication does not restore metaplastic tissue to histologically normal tissue, H. pylori eradication can change the cellular phenotype of metaplasia. Therefore, further studies investigating the effectiveness of H. pylori eradication in patients with metaplasia are needed [38].

In addition, the risk of metachronous cancers was also decreased after H. pylori eradication, especially in patients who underwent endoscopic early gastric cancer resection, most of whom had atrophic gastritis and/or intestinal metaplasia. Another randomized trial that investigated the long-term effects of H. pylori eradication therapy on the prevention of metachronous gastric cancer in Korea also showed that eradication reduced the risk of recurrent gastric cancer in the remaining stomach after curative endoscopic resection [39]. Therefore, although the efficacy of H. pylori eradication in reducing the incidence of gastric cancer is higher in patients with a normal gastric mucosa or early in the precancerous cascade, recent reports support the possibility that gastric cancer risk reduction may occur in patients with atrophic and metaplastic changes.

This review highlights the significant correlation between H. pylori infection and the development of gastric cancer, confirming H. pylori as a pivotal risk factor for one of the most lethal malignancies worldwide. Several studies have demonstrated that eradication therapy not only decreases gastric cancer development but also delays the progression of gastritis to more severe gastric pathologies. Future research should focus on discovering methods that are more effective than H. pylori eradication for reducing or preventing gastric cancer, such as identifying other factors that influence gastric cancer or developing vaccines against H. pylori.