Despite the decline in incidence and mortality rates, gastric cancer (GC) remains the fifth most common cancer globally. GC caused approximately seven hundred and seventy thousand deaths in 2020 [1,2,3]. Asian countries generally have exceptionally higher incidence and mortality rates than other countries. Over 60% of GC has recently been reported in Eastern Asia [4]. Common risk factors for GC include Helicobacter pylori (H. pylori) infection, genetic alterations, race, diet, and lifestyle [5,6]. Specific inherited GC syndromes, such as hereditary diffuse gastric cancer (HDGC) caused by inactivating mutations in the tumor suppressor gene CDH1, may also lead to a higher risk of GC. It is estimated that 80% of patients with CDH1 mutation will develop GC [5].

Classification of GC is essential for improved diagnosis and treatment. GC is commonly classified in histology as intestinal, diffuse [7,8], and mixed type [8]. While the intestinal type is the most common, specific populations are more prone to diffuse types of GC [8]. The World Health Organization (WHO) has recently defined specific cancers based on their molecular phenotype and histological characteristics [9]. In some rare gastric tumors, specific driver mutations have been identified, such as the characteristic MALAT1–GLI1 fusion gene in gastro-blastoma and EWSR1 fusions in clear gastrointestinal cell sarcoma and malignant gastrointestinal neuroectodermal tumors [9].

In general, the molecular mechanism of GC involves the molecular pathogenesis from normal epithelia to early cancer and, finally, to advanced cancer and invasion metastasis [10]. Different histological types of GC may differ in genetic alterations. For example, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are more likely to occur in the intestinal type of GC [10]. The molecular features may further classify GC into different types, such as the Asian Cancer Research Group (ACRG) and The Cancer Genome Atlas Consortium (TCGA) [11]. The ACRG molecular classification adopted immunohistochemistry, while TCGA molecular classification adopted the next-generation sequencing technology [11].

The advances in diagnosis in certain developed countries has reduced GC incidences. For instance, in Japan, the Health Law for the Aged has extended GC screening across the country since 1983. Moreover, in recent times, endoscopic examinations have been increasingly used in Japan as a screening method for GC. Similarly, in the Republic of Korea, radiographic screening for GC has been used since 2000 [12].

Recently, new clinical treatments specific to different kinds or stages of GC have been developed, improving the survival of GC patients. Endoscopic submucosal dissection (ESD), which offers a faster recovery rate and involves lower costs, is used to treat patients with early GC rather than surgery [13]. Patients with human epidermal growth factor-2(HER2)-positive GC could receive Trastuzumab in first-line chemotherapy to better treat GC and increase life expectancy [14]. Apart from the above clinical treatments, advances in immune checkpoint inhibitors (ICI) have also been made in recent times. Innovative treatment methods that inhibits the programmed death (PD-1)/ programmed death-ligand 1 (PD-L1) axis with ICI are generally accepted to be an effective way to treat advanced GC in the future [15].

Meanwhile, with a high expression mRNA level and the exposure of epitopes in malignant transformation, Claudin 18.2 (CLDN18.2) was identified as a promising therapeutic target for GC treatment. Clinical trials of Claudin 18.2-targeted monoclonal antibody are in progress [16]. Hence, it would be an ideal candidate for monoclonal antibody binding with the capability of reducing off-target effects.

Scientists and clinicians have developed new platforms for GC research and drug screening. One possible approach is to examine genetics in gastric stem cells in organoid models [17]. Patient-derived xenografts (PDX), a novel platform for translational cancer research, could help to investigate the major molecular features of tumors [18].

GC is notably more prevalent in Asian countries compared to other regions. As shown in Figure 1, the International Agency for Research on Cancer of the World Health Organization (https://gco.iarc.fr/; accessed on 3 April 2023) reported that the age-standardized incidence rate of GC per 100,000 in Eastern Asia was approximately two times that of other regions, such as Europe (Figure 1). The high prevalence of GC in Eastern Asia may be due to H. pylori seroprevalence rate, H. pylori oncogenic genes, dietary habits, and tobacco smoking.

Infection with H. pylori, a class I carcinogen, is one of the most critical risk factors for GC [19,20]. From 2000 onwards, the prevalence of H. pylori has reduced in Europe but not in Asia [21].

Globally, H. pylori infection rate for males was 46.3%, while for females it was 42.7% [22]. Asian countries have a higher seroprevalence rate of H. pylori than others, meaning more people in Asia have contracted H. pylori before. For example, Republic of Korea in Asia recorded a seroprevalence rate of H. pylori at 59.6% [23]. It was only 32.5% for the United States of America [24], a non-Asian country.

Several studies have shown that H. pylori eradication may significantly decrease incidence rates in Asian countries. A study conducted two randomized, placebo-controlled factorial-design intervention trials in a high-risk GC county in China. The study reveals that H. pylori eradication could decrease the likelihood of precancerous gastric lesions and lower the risk of developing GC [25]. Another study also suggested that H. pylori testing and eradication in East and South Asia resulted in 4,966,115 mean disability-adjusted life years gained [26].

A relatively large-scale H. pylori eradication trial has also supported that mass eradication could dramatically reduce GC without known detrimental consequences. On Matsu Islands in Taiwan, a place with a high risk of H. pylori infection, an extensive eradication was conducted between 2004 and 2018. The coverage percentage was 85.5% after six rounds of comprehensive scanning and eradication. Subsequently, H. pylori prevalence decreased from 64.2% to 15.0%. This corresponds to 53% effectiveness in reducing GC incidences compared with 1995 to 2003 [27].

Despite the dramatic reduction in GC incidences achieved through eradicating H. pylori, a large proportion of people infected with it are asymptotic [28]. Only 1–2% of the infected people develop gastric adenocarcinoma [29]. There is a high prevalence rate for H. pylori in Africa but a low GC incidence rate [30]. This gap may be because H. pylori contain different strain that may affect developing complications in GC.

The H. pylori genome encodes approximately 500 to 600 strain-specific genes, leading to different diseases [31]. These strains have been classified into highly virulent type I, intermediate, and reduced virulent type II strains [32]. One of the most important virulence factors is CagA, encoded by the CagA gene. Because of the connection between the bacteria’s adhesins on the surface and receptors of the bacterial portion on the host cells, CagA can adhere to the surface of gastric epithelial cells [33] and enter the cytoplasm of cells via the type IV secretion system [34,35]. Such an entry marks the first stage of CagA-caused diseases [36]. After penetrating the host epithelial cells, Src and Abl family kinases tyrosine-phosphorylate to some CagA molecules within several repeating Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs [35,37]. Both phosphorylated and non-phosphorylated CagA molecules were known to bind to host proteins and initiate pathogenic actions. Phosphorylated CagA interacts with the SH2 domain, which causes infected host cells in vitro to undergo actin-cytoskeletal rearrangements, dispersion, and elongation due to H. pylori [38]. Unphosphorylated CagA may affect the tight junction of stomach cells [39]. In addition, CagA may inhibit autophagy [40] and activate NF-κB [41]. CagA also may elevate cytokine, e.g., IL8 production that promotes inflammation [40,41]. Such inflammation plays a crucial role in developing GC [42].

Several studies have shown that certain oncogenic strains of H. pylori may be more commonly found in Asia [25]. For example, Cytotoxin-associated gene A (CagA), a common virulence factor of H. pylori, is dominant in China [25,43].

Asian people typically prefer traditional processed, spicy, or smoked food. The Japanese make traditionally processed food, such as salted fish [44]. Traditional Chinese cuisines, such as sausage in chuan flavor and Chinese bacon, are usually smoked [45]. Koreans prefer salty and spicy food due to traditional factors [46]. These may increase the risk for the aforementioned H. Pylori infection and increase GC risk or promote the progress of GC into a more advanced stage [19,46,47,48], leading to a higher prevalence of GC in Asia.

One reason behind the correlation between high salt intake and GC is that salt could impede the stomach’s mucosal barrier, causing inflammation [6,46]. In an infected model with H. pylori and high salt intake, mice developed gastric tumorigenesis in less than a year [47]. Humans also exhibit a similar pattern. Meta-cohort studies conducted in the Republic of Korea show that people who eat more salty food have a higher risk of developing non-cardia GC [49]. In recent years, an Asian endoscopy investigation also found that people who consume more salt may be more likely to develop atrophic gastritis with intestinal metaplasia [50].

Smoked meat also imposes a higher risk for GC by forming polycyclic aromatic hydrocarbons [50]. A meta-analysis of 11 studies has shown that regular consumption of smoked meat raised the risk for GC by 22% [48]. Carcinogenic capsaicin inside spicy food may cause mucosal damage and contribute to a higher risk for GC [46].

According to Statista, the three countries with the most significant number of smokers worldwide (i.e., China, India, and Indonesia) are in Asia. Tobacco smoking is positively correlated with GC [48,51]. Smoke contains various carcinogens, including N-nitroso-compounds, that may increase GC risk [52]. Another major substance is nicotine in tobacco, which may promote the proliferation and migration of GC cells by releasing prostaglandin E2, COX-2, VEGF, and ERK. It may also activate ERK and a COX-2-dependent rise in VEGF and VEGF receptors [53].

Meta-analysis of a cohort study revealed that compared to men who never smoked, the risk is elevated by approximately 60% in men who smoke and about 20% in women who smoke [49]. Another project, the “Stomach Cancer Pooling Project”, illustrates that the risk of GC increases with the number of cigarettes smoked daily and the duration of smoking [54].

Heavy alcohol consumption is generally positively associated with the risk of GC. Specifically, people consuming over 45 g of alcohol daily are usually considered to be drinking alcohol heavily and are more at risk for GC [55]. Alcohol dehydrogenase metabolizes ethanol of alcohol into acetaldehyde, which may cause persistent damage to DNA strands and hinder DNA repair processes [56]. Regarding light alcohol consumption, some studies argued that individuals who consume alcohol to an average amount (e.g., equal to or less than four drinks) have a similar risk for GC to people who do not drink at all [57,58]. In contrast, others consider that alcohol consumption would increase the risk of GC [59].