Early screening and risk factors for gastric cancer

Abstract

Gastric cancer (GC) has the highest incidence of digestive tract malignant tumors worldwide and ranks fifth in terms of cancer-related mortality and morbidity worldwide. Early diagnosis is the key to improving the prognosis of GC patients. The 5-year survival rate of patients with early GC can reach more than 90%, while 5-year survival rate during tumor progression is less than 30%. Therefore, promoting technological innovation and the application of early screening are highly important. In this article, the main risk factors for GC are systematically identified, among which Helicobacter pylori (H. pylori) infection is the clearest core trigger. In addition, other risk factors include lifestyle factors such as a high-salt diet, processed meat intake, smoking and drinking, and genetic factors such as a family history of GC among first-degree relatives. Moreover, this article reviews the current mainstream GC screening methods, including serum biomarker detection, liquid biopsy, H. pylori detection, imaging examination and endoscopy, in detail and analyses the sensitivity, specificity, advantages and limitations of each method. This article aims to provide a reference for clinical practice and research directions for the early screening of GC.

Key Words: Gastric cancer; Risk factors; Screening method; Liquid biopsy; Esophagogastroduodenoscopy

Core Tip: This paper provides a systematic review of risk factors and screening methods for gastric cancer (GC). The review demonstrates that GC development results from the synergistic effects of multiple factors, with Helicobacter pylori infection being the most clearly established class I carcinogen. Gastroscopy remains the gold standard for GC screening. With the future advancement of liquid biopsy and endoscopic techniques, it is anticipated that the early detection rate of GC will significantly improve, mortality rates will decrease, patient prognosis will be enhanced, and the global burden of GC will be alleviated.

INTRODUCTION

Gastric cancer (GC) ranks fifth in terms of cancer-related mortality and incidence rates worldwide. According to data from the International Agency for Research on Cancer (GLOBOCAN 2020), approximately 1.089 million new cases of GC and 769000 deaths occurred worldwide, accounting for approximately 5% and 4% of the total cancer incidence and deaths worldwide, respectively[1]. The incidence rate varies significantly across different regions, with the majority of cases concentrated in East Asia[2]. Significant differences in the burden of GC have been observed among the sexes. A study revealed that the numbers of new cases, deaths, and disability-adjusted life years (DALYs) among men were significantly greater than those among women[3]. In 2021, the number of new cases among men was 2.1 times higher than that among women, the number of deaths was 1.89 times higher than that among women, and the DALYs were 2.03 times higher than those among women. These differences may be closely related to lifestyle factors such as increased smoking and drinking rates among men. Approximately 1 million new cases are diagnosed worldwide every year, resulting in more than 650000 deaths[4]. A total of 1.77 million new cases and 1.27 million deaths will occur worldwide by the year 2040. The early diagnosis and treatment of GC are crucial for improving the prognosis of patients. Currently, the United States lacks a nationwide GC screening program. More than one-third of American patients are diagnosed with GC after metastasis, with a median survival of 6 months and a 5-year survival rate of only 32%[5]. Compared with the United States, GC is diagnosed at an early stage and survival rates are superior in Japan, with a 5-year survival rate as high as 70.2%[6], which may be related to the promotion of early detection by its GC screening program. The Japanese Treatment Guidelines (2021 Edition) clearly set the screening age at 50 years with a screening interval of 2-3 years and recommend gastroscopy as the primary screening method. These standardized screening guidelines ensure scientific rigor and effectiveness, significantly increasing the probability of early GC (EGC) detection[7]. South Korea launched the National GC Screening Program in 2002 and issued national screening guidelines in 2015. Biennial gastroscopy or upper gastrointestinal (UGI) imaging has proven effective in reducing GC-related mortality[4]. China has not yet implemented a national GC screening program. Opportunistic endoscopic screening remains the primary method for early detection and prevention. By the end of 2018, more than 2 million rural residents had undergone endoscopic examinations, with a cancer detection rate of 2%, and 70% of patients were diagnosed at an early stage[8]. At present, the European guidelines recommend opportunistic screening for patients with established precancerous lesions but do not recommend screening the general population.

The occurrence of GC is the result of synergistic effects of multiple factors, among which Helicobacter pylori (H. pylori) infection is the clearest and main trigger. Although H. pylori infection is closely related to an increased risk of GC, only approximately 3% of infected people eventually develop GC, suggesting that other factors may also be involved in the carcinogenic process[9]. In addition, studies have shown that Epstein-Barr virus infection is associated with 5%-10% of GC cases[10]. In terms of eating habits, long-term intake of high-salt food, pickled food, and smoked barbecue and insufficient intake of fresh vegetables and fruits further increase the probability of GC. Genetic factors also warrant attention, as individuals with a family history of GC exhibit a markedly higher risk than the general population. Research showed that the lifetime risk of stomach cancer for CDH1 gene mutation carriers is approximately 70%-80%[11]. In addition, long-term smoking, excessive alcohol consumption, gastric polyps, chronic atrophic gastritis, gastric ulcers and other precancerous lesions, as well as obesity, long-term mental stress and other factors, increase the risk of GC to varying degrees.

The methods used to screen for GC primarily include serum biomarkers, liquid biopsy, H. pylori detection, imaging examinations, and endoscopic examinations. Serum biomarker assessments mainly focus on the combined measurement of indicators such as serum pepsinogen (PG) and gastrin-17 (G-17) levels to assess the risk of precancerous lesions such as gastric mucosal atrophy (GMA) and intestinal metaplasia. Due to its noninvasive nature, liquid biopsy enables early detection and dynamic monitoring of microscopic GC lesions through the detection of tumor-related substances in peripheral blood, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). As a class I carcinogen for GC, screening for the H. pylori infection status is a key step in the GC risk stratification, and eradication therapy can significantly reduce the risk of GC development. Imaging examinations are represented by abdominal computed tomography (CT), magnetic resonance imaging (MRI), and gastric ultrasound, which can clearly show the location, size and infiltration depth of gastric lesions, providing an important reference for clinical staging. Esophagogastroduodenoscopy (EGD) is the gold standard for the diagnosis of GC. It can directly observe the morphology of gastric mucosal lesions and collect tissues for pathological biopsy to clarify the nature of the lesions. Gastroscopy combined with endoscopic auxiliary techniques such as pigment endoscopy, magnified endoscopy, and narrowband imaging (NBI) technology can further increase the rate of EGC detection. This article aims to systematically identify the current risk factors and screening methods for GC, as well as future development directions.

RISK FACTORS FOR GC

H. pylori

H. pylori is a gram-negative, spiral, microaerobic bacteria. It not only specifically colonizes the gastric epithelium but can also enter the deep layers of the gastric gland, establish tiny colonies in stem cells and progenitor cell areas, induce local tissue proliferation and promote pathological progression[12]. H. pylori infection is a risk factor for GC (75% of the attributed risk) and is classified as a carcinogen by the World Health Organization[13]. Multiple meta-analyses have shown that H. pylori infection can significantly increase the risk of GC [relative risk (RR) = 4.36, 95% confidence interval (CI): 3.54-5.37][14]. Generally, H. pylori is believed to trigger the Correa cascade reaction to promote ERC initiation from normal gastric mucosa to nonatrophic gastritis, chronic atrophic gastritis, intestinal epithelial metamorphosis, intraepithelial tumors and intestinal GC[15]. Recent research has shown that the virulence factor H. pylori can activate the signal transducer and activator of transcription 3, nuclear factor-κB, extracellular signal-regulated kinase, protein kinase B and Wnt/β-catenin signaling pathways and plays key roles in abnormal signaling, movement and proliferation, cytoskeletal rearrangement and the disruption of cell polarity, ultimately contributing to the development of GC[16] (Figure 1). Meta-analyses revealed that compared with patients who did not undergo H. pylori eradication therapy, the incidence and mortality rates of patients with GC were significantly reduced by 46% [RR = 0.54; 95% confidence interval (CI): 0.40-0.72] and 39% (RR = 0.61; 95%CI: 0.40-0.92) after H. pylori eradication therapy, and H. pylori eradication also reduced the risk of metachronous GC in patients who underwent gastrectomy for gastric tumors[17]. These results were consistent with the findings reported by Ford et al[18].

Figure 1 Mechanism of H. pylori-induced gastric cancer. A: The Correa cascade illustrates the histopathological progression from normal gastric mucosa to gastric cancer over time; B: Molecular mechanisms of H. pylori infection, highlighting key virulence factors and signaling pathways (e.g., signal transducer and activator of transcription 3, nuclear factor-κB, mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinases/protein kinase B, β-catenin) that promote cytoskeleton rearrangement, loss of cell polarity, and enhanced migration/invasion, ultimately contributing to gastric cancer development. STAT3: Signal transducer and activator of transcription 3; NF-κB: Nuclear factor-κB; MAPK: Mitogen-activated protein kinase; ERK: Extracellular signal-regulated kinase; Akt: Protein kinase B; PI3K: Phosphoinositide 3-kinases; H. pylori: H. pylori.

Eating habits

Long-term high-salt diets and the consumption of red meat and processed meat are risk factors for GC. A dose-response meta-analysis revealed that the risk of GC in the high-salt diet group was 1.24 times higher than that in the low-salt diet group[19]. Excessive sodium intake can damage the gastric mucosa, leading to hyperosmolarity within the stomach. This damage causes widespread diffuse pathological changes in the gastric mucosa, including congestion, edema, erosion, ulceration, necrosis, and bleeding, thereby increasing the risk of GC[20]. The risk of GC was highest when 150 g of red meat was consumed (hazard ratio = 1.85; 95%CI: 1.56-2.20)[21]. Some components in red meat, such as heme iron, nitrite, and polycyclic aromatic hydrocarbons, may promote the development of GC by inducing oxidative stress, causing DNA damage, and interfering with the barrier function of the gastric mucosa[22]. Other dietary risk factors include insufficient intake of dietary fiber[23], excessive intake of refined grains[24], and insufficient intake of antioxidant vitamins.

Smoking

Smoking is a group 1 carcinogen for GC. Praud et al[25] reported that current smokers face a 25% increased risk of GC, with the risk increasing with increasing smoking duration. Cigarette smoke-induced exosomes increase stemness gene expression, the epithelial-mesenchymal transition, and GES-1 cell proliferation, thereby accelerating GC progression[26].

Drinking

Alcohol consumption is a risk factor for GC, particularly among heavy drinkers whose daily intake is ≥ 30 g. A meta-analysis demonstrated that alcohol intake is significantly associated with an increased risk of GC (odds ratio = 1.20, 95%CI: 1.12-1.27)[27]. Acetaldehyde, a metabolite of ethanol, exerts a potent corrosive effect on the gastric mucosa. It disrupts the gastric mucus-bicarbonate barrier, thereby disturbing the physiological environment essential for normal gastric mucosal metabolism. Related studies have shown that both short-term heavy drinking and long-term chronic alcohol consumption can alter gastric acid secretion and induce acute gastric mucosal damage by mediating the release of inflammatory factors, granulocyte activation, protease secretion, reactive oxygen species production, vasoconstriction, and increased vascular permeability[28].

Genetic factors

A family history of GC among first-degree relatives is a risk factor for GC. A recent meta-analysis of 21 studies indicated a significant correlation between the GC risk and first-degree relatives with a history of GC, with an odds ratio of 2.92[29]. Approximately 40% of hereditary diffuse GCs are caused by loss-of-function mutations in the CDH1 gene[30]. Whole-exome sequencing analysis also revealed germline mutations in genes other than CDH1, such as alterations in the tumor suppressor genes SDHB, CTNNA1, STK11, and the DNA repair-related genes PALB2, BRCA2, and ATM. Furthermore, patients with syndromes affecting DNA repair genes (TP53 and APC) and tumor suppressor genes (BRCA) exhibit increased susceptibility to GC[31]. Familial adenomatous polyposis is also associated with an increased risk of GC[32].

Others

Other factors include changes in the gastric microbiota. Multiple studies have indicated that microbial diversity gradually decreases during GC development but is higher in tumor tissues than in nontumor tissues, suggesting an interaction between the microbiota and cancer[33].

SCREENING METHODS

Serum biomarker

Tumor markers: Tumor markers are substances that are produced abnormally by tumor cells or the host response. They reflect the generation, development, and treatment of tumors. Carcinoembryonic antigen (CEA) and carbohydrate antigens (CA), such as CA724, CA125, and CA199, are primarily used to monitor treatment efficacy and the prognosis rather than the early detection or screening of GC[34]. Although these markers are elevated in patients with GC, their diagnostic sensitivity and specificity remain low[35]. Yang et al[36] reported that the sensitivities of CA724, CEA, CA125, and CA199 alone for GC were 33.0%, 25.5%, 31.1%, and 38.7%, respectively. The sensitivity of their combined detection was 66.0%, which has not yet reached the standard required for the effective identification of GC[36]. The limitation of using these markers is that they are not only expressed in tumor tissues but are also susceptible to changes induced by benign diseases, inflammation, the physiological state, individual differences, detection factors, etc., thus increasing the occurrence of false positive results. Therefore, the identification of more effective biomarkers is key for improving the prevention of GC and its prognosis.

Biomarkers of gastric function: Biomarkers of gastric function primarily include PG, the PGI/PGII ratio, and G-17. PG is a noninvasive marker that can indicate the state of the gastric mucosa and produces two biochemically different types of PG, PGI and PGII, which are good indicators of the exocrine function of the gastric sinus mucosa. PGI is produced primarily in the fundus mucosa, whereas PGII originates from the fundus, paranasal sinuses, cerebral ventricles, and duodenal mucosa[37]. Given their noninvasiveness, convenience, and low cost, gastric function biomarkers have become the preferred method for large-scale population screening for GC. They can indicate the risk of GC by reflecting the status of gastric mucosal function, but their diagnostic specificity and sensitivity are still limited by benign gastric diseases. A meta-analysis revealed that the sensitivity of PG screening for GC is 57%-59%, and the specificity is 73%-87%[38]. Despite the lower sensitivity of PG, a single serum PG screen at age 40 demonstrates greater cost-effectiveness than no screening[39]. G-17 serves as a sensitive indicator of gastric antral endocrine function, revealing antral mucosal atrophy or abnormal proliferation[40]. A meta-analysis indicated that PG displayed a sensitivity of 0.70 (95%CI: 0.64-0.76) and a specificity of 0.93 (95%CI: 0.90-0.95) for diagnosing EGC[41]. A study revealed that combining H. pylori detection with the plasma levels of PG and G-17 was more valuable for the diagnosis of a precancerous state and GC[37]. GastroPanel is a method that assists in diagnosing gastric mucosal diseases by measuring and comprehensively analyzing the levels of G-17, PG I and II, the PG ratio, and anti-H. pylori IgG antibodies. When GastroPanel was used to detect gastric atrophy or GC, the sensitivity and specificity of a PG I/II ratio ≤ 5.3 ranged from 51% to 59% and 61% to 66%, respectively[42]. The clinical utility of gastric function markers requires further validation while considering population baseline characteristics, optimizing detection thresholds, and developing combined diagnostic models, which are expected to further expand its scope of application in GC screening.

Liquid biopsy

In recent years, liquid biopsy has shown tremendous potential in precision medicine. Its minimally invasive nature enhances patient screening compliance and enables real-time monitoring of tumor dynamics, which is crucial for early diagnosis, disease prognosis, recurrence predictions, and even treatment efficacy assessments[43]. Initially, liquid biopsy focused on CTCs in the blood but has now been expanded to include ctDNA, circulating cell-free DNA, noncoding RNAs, exosomes, and microRNAs (miRNAs). Although it has not yet been routinely used for the detection and monitoring of GC, liquid biopsy is being increasingly used in patients with advanced disease, especially those who are not suitable for routine tissue biopsy[44].

CTCs: CTCs are free cancer cells that are shed from solid tumors into the bloodstream. They carry the complete genomic information of tumor cells and exhibit intact tumor cell morphology and cell membrane markers[45]. CTCs exhibit high tumor specificity and are noninvasive and suitable for repeated testing, which can be a valuable adjunct to the auxiliary diagnosis of GC[46]. Kang et al[47] demonstrated that a threshold of 2 CTCs per 7.5 mL of blood yielded sensitivity and specificity values of 85.3% and 90.3%, respectively, for distinguishing GC patients from healthy control subjects. These results show that CTCs may be used as a biomarker for the early diagnosis of GC. As a potential prognostic biomarker for GC, CTCs are significantly related to the progression of the disease and the prognosis of patients[48]. A randomized controlled trial (RCT) showed that CTCs were independent predictors of the progression-free survival and OS of GC patients[49]. At present, two main categories techniques exist for the enrichment and isolation of peripheral blood CTCs: Immunochemical methods based on surface markers and separation methods based on physical characteristics. Both methods have their own advantages and disadvantages. The former may lead to false negatives because of the lack of epithelial marker expression in CTCs, and the latter is prone to false positives because of the presence of certain benign conditions (such as inflammation). A comparison of the results of different studies is difficult because of the inconsistent technical standards of enrichment and identification, which is the greatest problem facing CTC research. Research on CTC detection is currently in a stage of exploration and early clinical validation, with some technologies being applied clinically in a limited manner. The CellSearch system has been approved by the Food and Drug Administration for use in assessing prognosis in patients with metastatic breast cancer, prostate cancer, and colorectal cancer, but it is not intended as a standalone diagnostic tool[50]. In addition, the half-life of CTCs is relatively short (approximately 1-2.4 hours), and the number of CTCs in the blood is low; thus, achieving high-specificity and high-sensitivity detection in patients with GC is difficult.

CtDNA: CtDNA constitutes a subset of cell-free DNA that primarily originates from tumor cell apoptosis or necrosis. It is typically detected using polymerase chain reaction (PCR)-based methods (such as quantitative real-time PCR and droplet digital PCR) and next-generation sequencing-based methods (such as CAPP-Seq and Guardant360). Next-generation sequencing-based methods enable the simultaneous detection of multiple genes and are suitable for a comprehensive genetic analysis, whereas PCR-based methods are suitable for the high-sensitivity detection of specific mutations[51]. CtDNA detection has certain potential in EGC screening. A comparative study showed that in EGC screening, a ctDNA analysis was more sensitive than the analysis of traditional serum markers (such as CEA, CA19-9, and CA72-4)[52]. Klein et al[53] developed an early detection method for multiple cancers based on ctDNA methylation, whose diagnostic sensitivities for patients with stage I, II, III and IV GC were 16.7%, 50.0%, 80.0% and 100.0%, respectively. The overall sensitivity was 51.5%, and the overall specificity was 99.5%. Another study revealed that the preoperative ctDNA level was positively correlated with the tumor stage and size. Yang et al[54] confirmed that ctDNA positivity in preoperative samples was significantly related to a high tumor T stage and that an increased tumor volume and tumor involvement of the lymph nodes and the portal vein were associated with high preoperative ctDNA levels. CtDNA can also predict the postoperative recurrence of GC. Among 20 patients with resectable GC who received perioperative chemotherapy or radiochemotherapy, 11 postoperative ctDNA-negative patients did not relapse after 42 months of follow-up, whereas 6 of the 9 patients in whom postoperative tumor-specific mutations were detected experienced recurrence[55]. Research by Nakamura et al[56] showed that compared with tissue genotyping, ctDNA genotyping significantly shortened the patient screening time (11 days vs 33 days), improved trial enrollment rates (9.5% vs 4.1%), and did not compromise therapeutic efficacy. However, in patients with EGC, the detection sensitivity of ctDNA was low, resulting in a decrease in consistency to approximately 30%. This difference may be due to the low level of ctDNA released by early tumors, which affects its accurate detection. CtDNA mutation analysis is not being used in clinical practice for guiding targeted therapy[57]. The Food and Drug Administration has approved FoundationOne CDx for detecting ERBB2 (HER2) gene amplification in GC to guide anti-HER2 targeted therapy. Compared to methylation testing, its technical maturity is relatively low, and optimization of detection algorithms and standardized procedures remains necessary[58].

DNA methylation: DNA methylation refers to a chemical modification catalyzed by DNA methyltransferases where the methyl group from S-adenosylmethionine is transferred to specific bases within the DNA strand[59]. A study revealed that the methylation level of multiple tumor-associated genes in the serum or plasma DNA of GC patients was significantly increased[60]. RNF180 is an E3 ubiquitin ligase. Cheung et al[61] employed a genome-wide methylation analysis and identified RNF180 as a novel DNA methylation biomarker in GC, with preliminary validation demonstrating 76% sensitivity and 100% specificity in GC tissue samples. Further validation in plasma samples from patients with GC confirmed that RNF180 has high sensitivity (56%-63%) and specificity (91%-100%). A multicenter cohort study revealed that the sensitivity of RNF180 and SEPTIN9 gene methylation increased with tumor progression, and its detection sensitivity for EGC reached 50.9% and 61.8%, respectively, values that are far higher than those of the protein tumor markers CEA (6.17%), CA199 (3.70%), and CA125 (10.26%)[62]. Therefore, a combined analysis of plasma RNF180 and SEPTIN9 methylation levels can be used to monitor the disease progression of early-stage GC. At present, research on DNA methylation in GC is developing rapidly. As a noninvasive detection method, a variety of liquid biopsy detection kits for DNA methylation have been successfully applied in the clinical screening and diagnosis of GC.

Non-coding RNAs: Non-coding RNAs are a class of RNA molecules that do not encode proteins, including miRNAs, long noncoding RNAs (lncRNAs), circular RNAs (circRNAs) and other special types, which play important roles in the occurrence, development, diagnosis, treatment and prognosis of GC[63].

MiRNAs are a class of endogenous noncoding small RNA molecules composed of 17-25 nucleotides that regulate the expression of target genes through complementary base pairing and widely participate in cell proliferation, differentiation, apoptosis and other processes. Their stability in serum makes liquid biopsy suitable as a diagnostic and prognostic biomarker for GC[64]. Compared with other noninvasive methods, a large-scale prospective multicenter study developed a 12-miRNA biomarker panel for GC diagnosis, which showed superior diagnostic accuracy to other non-invasive methods [area under the curve (AUC) value of 0.84, compared with 0.63 for H. pylori serology and 0.64 for the ABC method][65]. GASTROClear uses a 12-miRNA biomarker panel detected in serum and became the first approved molecular blood test for the early detection of GC in high-risk people, with a sensitivity of 87.0% and specificity of 68.4%[66]. Izumi et al[67] found that the combined detection of miR-18a, miR-181b, and miR-335 showed high diagnostic accuracy for GC across all patients (AUC = 0.86; 95%CI: 0.83-0.90), including patients with stage I tumors (AUC = 0.85; 95%CI: 0.79-0.91). However, as the study samples were primarily obtained from Japan, further validation is needed to determine whether these results apply to other regions and populations.

LncRNAs are a class of RNA transcripts exceeding 200 nucleotides in length that lack protein-coding functions. They are widely involved in various pathological processes in the body. LncRNAs influence tumorigenesis through complex signaling pathways and interact with miRNAs[68]. Research has shown that their expression levels can predict the biological behaviors of GC cells, including invasion, metastasis and the prognosis[69]. Chen et al[70] studied a combination of four lncRNAs (CEBPA-AS1, INHBA-AS1, AK001058 and UCA1) and two miRNAs (PPBP and RGS18) and observed that three lncRNAs (INHBA-AS1, A K001058 and UCA1) and one miRNA (RGS18) had the best diagnostic efficacy, with an AUC of 0.820, sensitivity of 0.782, and specificity of 0.708. Similarly, Petkevicius et al[71] reported the carcinogenic effect of an antisense RNA targeting the lncRNA HOX on EGC. The lncRNA HLA complex P5 (HCP5) is a noncoding RNA. The AUC of serum lncRNA HCP5 levels for distinguishing patients with GC from healthy control subjects was 0.818 (95%CI: 0.757-0.880; sensitivity 80%; specificity 70%). Furthermore, the combined diagnostic panel of HCP5, CEA, and CA19-9 achieved a maximum AUC of 0.870 (95%CI: 0.819-0.921), with 81% sensitivity and 79% specificity[72]. The results of this study revealed that lncRNAs also have potential for use in GC screening. However, as novel biomarkers for EGC screening, these molecules may still require additional research and refinement to achieve optimal clinical application.

CircRNAs are a class of rich endogenous noncoding RNAs characterized by covalently closed circular structures and stable biological properties that facilitate detection[73]. Ma et al[74] reported that the AUC of circPTPN22 for the diagnosis of GC was 0.857, the sensitivity was 78%, the specificity was 84%, the total accuracy was 80%, the positive predictive value was 84%, and the negative predictive value was 76%, all of which were higher than those of the above corresponding indicators for CEA and CA19-9 alone. When combined with CEA, the AUC of circPTPN22 reached 0.878, while its AUC value in combination with CA19-9 was 0.866. Roy et al[75] combined 8 circRNAs to construct a model to predict the EGC risk, with an AUC of 0.87, a sensitivity of 0.783, and a specificity of 0.783. These findings provide a theoretical basis for the clinical application of circRNAs as biomarkers for EGC. Liu et al[76] developed novel paper-based analytical devices for the ultrasensitive detection of two GC-associated RNA biomarkers (miRNA-21 and circRNA-HIAT1). The study revealed that using miRNA-21 alone yielded an AUC of 0.78 for a GC diagnosis. When miRNA-21 was combined with circRNA-HIAT1, the AUC increased to 0.98, with a Youden index of 0.90, indicating a significant increase in GC screening specificity. In summary, compared with conventional tumor markers, circRNAs demonstrate higher sensitivity and specificity as liquid biopsy biomarkers for GC. Combined detection with protein biomarkers such as CEA and miRNAs may increase the diagnostic accuracy. Due to the lack of large-scale clinical validation and the absence of standardized testing methods, no products have been widely approved for clinical application. CircRNA-based liquid biopsy technology holds promise for EGC screening and diagnosis and should be implemented clinically.

H. pylori detection

H. pylori eradication therapy is crucial and can serve as an adjunct to endoscopic screening and surveillance for primary and secondary prevention of GC. Opportunistic screening for an active H. pylori infection should be considered for individuals deemed to have an increased risk of GC. A screen for H. pylori infection should also be considered for adult household members of H. pylori-positive individuals[5]. The Taipei guidelines recommend screening for H. pylori among individuals aged 20 years to 40 years[77]. Large-scale meta-analyses integrating RCTs and high-quality observational studies have confirmed that the eradication of H. pylori infection can not only effectively reduce the risk of GC but also reduce GC-related mortality, establishing the clinical value of this preventive strategy[18]. Lucero et al[78] demonstrated that H. pylori eradication provides significant protection against GC development (hazard ratio = 0.57, 95%CI: 0.33-0.98). The combination of H. pylori fecal antigen and fecal immunochemical test can reduce the incidence of GC[79]. A meta-analysis revealed that compared with a lack of H. pylori eradication, H. pylori eradication therapy can reduce the RR of GC by 45% (RR = 0.55; 95%CI: 0.46-0.67; P < 0.001)[80].

Among noninvasive H. pylori detection tests used in clinical applications, the urea breath test (UBT) is the preferred method, but it is often not available in remote areas with limited resources. Chiang et al[81] developed a rural-to-central artificial intelligence (AI) model that automatically assesses H. pylori infection and gastric precancerous lesions using routine UGI endoscopy images to bridge healthcare resource gaps. The AI model displayed an accuracy of 92.8% (95%CI: 88.9%-96.6%) for H. pylori infection, 88.6% (95%CI: 87.2%-90.0%) for atrophic gastritis, and 88.0% (95%CI: 86.5%-89.5%) for intestinal metaplasia. However, UBT is relatively costly, and monoclonal fecal antigen tests may serve as alternatives. Serological H. pylori detection tests can be used to screen high-risk populations[82]. An economic benefit analysis revealed that if global population screening and treatment are implemented, more than 8.7 million DALYs can be reduced, and East Asia will benefit the most[17]. Although H. pylori eradication reduces the risk of GC in high-risk individuals, it is not recommended as a routine preventive measure for low-risk individuals without other risk factors.

Imaging examinations

Gastric ultrasound: Gastric ultrasound is a noninvasive, convenient and radiation-free screening method for GC. It can clearly show the layered structure of the gastric wall and assess the depth of invasion, serving as a valuable supplement to GC T staging. Compared with the postoperative pathology results, the diagnostic accuracy of preoperative gastric ultrasound for stages T1a, T1b, T2, T3, T4a and T4b was 76.6%, 69.6%, 62.7%, 60.8%, 88.0% and 88.7%, respectively, and the overall accuracy was 75.5%[83]. A meta-analysis showed that compared with contrast-enhanced CT, double contrast-enhanced ultrasound demonstrated higher sensitivity and specificity for staging T1 to T4 GC, particularly for the T1 and T4 stages[84]. In addition, another study revealed that gastric ultrasound and double contrast-enhanced ultrasound can effectively distinguish between GCs ≤ T1 stage and those ≥ T2 stage[85]. However, gastric ultrasound has low sensitivity for detecting EGC, is susceptible to interference from gastric gas and operator skill, and tissue specimens cannot be obtained for pathological examinations.

UGI: UGI shows the morphology and lesions of the esophagus, stomach and duodenum through X-ray irradiation after the patient consumes the barium sulfate contrast agent and can dynamically observe gastrointestinal motility. A study revealed that the sensitivity of UGI for detecting GC was 36.7%, and the specificity was 96.1%[86]. Air-barium double contrast is successively introduced with gas and barium contrast. The gas distends the lumen, followed by uniform coating of the mucosal surface with barium to reveal fine mucosal structures and minute abnormalities. It can identify malignant gastric ulcers and invasive lesions. The false negative rate can reach 50%, and the sensitivity to EGC is as low as 14%[87]. Moreover, UGI series is radioactive and lacks a biopsy capability. Given the widespread availability of EGD and CT, UGI is no longer popular as a diagnostic method for GC. Japan launched UGI as early as the 1960s and promoted it to the whole country in 1983. Many subsequent studies have confirmed that EGD is better than UGI for reducing the death rate. In 2014, the Japanese guidelines established EGD as a recommended screening method, recommending that people over 50 years old be screened using this test every two years. In 1999, South Korea implemented a national cancer screening program that recommends EGD or UGI every two years for people over 40 years old. With the accumulation of evidence, South Korea gradually abolished the use of UGI and retained only EGD. UGI has low detection sensitivity for EGC. Tiny mucosal lesions and submucosal infiltration foci are difficult to identify, and histological specimens cannot be obtained for a pathological diagnosis. At present, it is mostly used as a supplementary method to gastroscopic screening and is not the preferred approach.

CT: CT, as a noninvasive imaging screening method, is valuable for assessing the depth of invasion and metastatic status of GC. A meta-analysis indicated that the diagnostic accuracy of CT for the T stage of GC was 77.1%-88.9%; for serous involvement, its sensitivity and specificity reached 82.8%-100% and 80%-96.8%, respectively[88]. However, its limitations, a low detection rate for EGC and radiation exposure, restrict its standalone application. In recent years, AI has emerged as a transformative innovation in gastroenterology. It has broad applicability, ease of use and minimal training requirements. It can assist operators regardless of their experience or resources and has a wide range of access. China developed the world’s first AI model, GRAPE, for screening GC imaging data. The initial screening rate of people at high risk of GC has reached 24.5%, and approximately 40% of the detected cases were patients with asymptomatic GC. The detection rate of GRAPE increases with advancing tumor T stage[89]. This model is the first to use plain CT scans to identify EGC lesions, which indicates that GC screening can be conducted similar to pulmonary nodule screening and has strong potential for large-scale GC screening, which can improve the cost-effectiveness and compliance of screening and ultimately reduce GC mortality. However, its sensitivity for EGC detection is limited, and large-scale prospective studies are still needed to further validate the efficacy of GRAPE in GC screening.

MRI: MRI is not the preferred modality for GC screening, but its superior soft tissue resolution enables the clear visualization of the gastric wall invasion depth, perigastric tissue involvement, and distant metastases, providing precise imaging evidence for tumor staging. Li et al[90] compared the application of CT and MRI in GC staging and found that the diagnostic accuracy of MRI for GC T staging (61%-77% vs 50%-64%) and N staging (54%-68% vs 51%-57%) is significantly better than that of conventional CT. MRI is shows particularly greater accuracy for T1 stage (81% vs 63%), T4a stage (79% vs 68%), N1 (41% vs 24%) and N3 (64% vs 45%) GC than CT. Diffusion-weighted imaging is superior to morphological measurements for detecting lymph node metastasis. An ADC value truncation value of 1.39 × 10^-3 mm²/second can distinguish metastatic lymph nodes (sensitivity 85.7%). For distant metastases (such as peritoneal or hepatic metastases), the accuracy of diffusion-weighted imaging is comparable to that of positron emission tomography/CT[91]. This technology is free of ionizing radiation and is suitable for individuals allergic to iodine contrast agents or those who must avoid radiation. However, its limitations include a prolonged examination duration, insufficient sensitivity for detecting early mucosal microlesions, and the inability to obtain pathological specimens. It is mostly used as a supplementary examination to assess tumor progression following endoscopic screening and diagnosis.

Endoscopic examinations

Endoscopic ultrasonography: Endoscopic ultrasonography (EUS) is a minimally invasive examination that integrates endoscopy with ultrasound technology. It has two advantages: Direct visualization of mucosal lesions during endoscopy and ultrasound assessment of gastric wall layers and surrounding tissue invasion. It also has high accuracy in determining the depth of submucosal invasion in EGC and distinguishing precancerous lesions and can accurately locate enlarged perigastric lymph nodes. It provides critical evidence for clinical staging and treatment planning. The accuracy of EUS for T1 lesions is nearly 100%, especially linear EUS, and the overall T-stage accuracy is 50%-90%. However, its accuracy is lower for T2 lesions, particularly those located in the anterior wall or cardia, where over- or under-staging may occur. EUS significantly outperforms CT in assessing the invasion depth[92]. Uema et al[93] developed an AI-based EUS-assisted diagnostic model for assessing the depth of invasion in EGC. In terms of diagnostic performance, the AUC of the AI model was 0.815 (95%CI: 0.743-0.886), and the accuracy, sensitivity and specificity were 74.1%, 73.1% and 75.0%, respectively, which were comparable to those of real-time expert diagnosis. Its limitations include high technical demands, time-consuming procedures, and the inability to directly replace pathological biopsy. Clinically, it is primarily used for further evaluation after the endoscopic detection of suspicious lesions, particularly for determining the suitability for endoscopic resection, and serves as a crucial bridge between GC screening and precision treatment.

Capsule endoscopy: Capsule endoscopy (CE) requires no intubation or anesthesia. With the ability to autonomously traverse the digestive tract and capture real-time images, it has unique application value and development potential in GC screening. However, CE has limitations, such as a reliance on digestive tract peristalsis and the inability to actively control the lens direction. Thus, magnetically controlled CE (MCCE) has emerged. MCCE is a CE system that actively manipulates the position and orientation of the capsule via an external magnetic field to achieve the comprehensive visualization of the gastric mucosa. A meta-analysis of a total of 1324 subjects included in 9 studies showed that compared with that of conventional gastroscopy, the combined sensitivity of various MCCE methods was 88% (95%CI: 85%-91%), and the combined specificity was 82% (95%CI: 78%-86%). Among these methods, NaviCam magnetic CE had the largest sample size and showed superior diagnostic performance, achieving an overall sensitivity of 92% (95%CI: 88%-95%) and a specificity of 90% (95%CI: 87%-93%)[94]. Current comparative studies focus primarily on detecting gastric lesions, and some of them involve the detection of esophageal or UGI tract lesions. The overall diagnostic accuracy is high, showing 86.8%-96.2% concordance with conventional gastroscopy for gastric disease detection, while resulting in superior patient tolerance compared with traditional endoscopy. Many studies have shown that MCCE can detect lesions missed by conventional endoscopy[34]. Despite these advances, MCCE remains limited. Biopsies cannot be performed and therapeutic interventions cannot be administered, gas or water cannot be injected, and this method struggles to control capsule movement through the pylorus. MCCE serves as a valuable adjunct to conventional endoscopy for examining the stomach and other UGI tract structures.

EGD: EGD is the gold standard for GC screening. Since the advent of fiber gastroscopy in the 1960s, technical advancements such as electronic gastroscopy, high-definition endoscopy, and AI-assisted systems have significantly improved the detection rate of EGC. According to the Korea National Cancer Screening Program, the sensitivity and specificity of EGD are 69.0% and 96.0%, respectively[86]. In Asia, endoscopic screening has been shown to reduce the risk of GC mortality by 40%[95]. Compared with controls, a single endoscopic screen reduced the incidence and mortality of UGI cancers among high-risk Chinese patients by 23% (RR = 0.77, 95%CI: 0.74-0.81) and 57% (RR = 0.43, 95%CI: 0.40-0.47), respectively[96]. In South Korea, endoscopic screening reduced the risk of GC mortality by 47% (odds ratio = 0.53; 95%CI: 0.51-0.56)[97]. However, limitations such as overdiagnosis, potential complications, and access to specialized endoscopists and equipment constrain the widespread adoption of EGD screening. Preliminary data suggest that routine endoscopy quality may differentially impact the incidence of GC through a more meticulous assessment and improved detection of precancerous lesions[98]. A global meta-analysis revealed an overall miss rate of 9.76% for UGI cancers in EGD screening, with some studies reporting rates as high as 25.75%[99]. These findings underscore the necessity of establishing quality control standards for upper endoscopy, including standardized preprocedure fasting guidelines, minimum examination duration requirements, and comprehensive imaging documentation of anatomical landmarks and lesions to minimize the number of blind spots.

EGC has a variety of endoscopic manifestations due to variations in lesion characteristics, stage, and underlying mucosal conditions. White light imaging (WLI) is the main method for detecting EGC. The sensitivity of WLI to GC and precancerous lesions such as intestinal metaplasia and dysplasia was 74.6%, the specificity was 94%, and the accuracy was 88%[100]. However, the emergence of multiple emerging endoscopic technologies, such as image enhancement, real-time diagnostic technology, and AI-assisted endoscopy technology, enables endoscopists to obtain more detailed information about lesions, guide targeted biopsies, and increase the diagnostic accuracy of precancerous lesions.

Image enhancement has significantly improved the detection rate and accuracy of EGC[101]. By illuminating the mucosal layer with narrow-band blue-green light, NBI can significantly improve the visibility of the mucosal surface structure and vascular patterns and clearly reveal the microvascular and microsurface morphology of the gastric mucosa[102]. A meta-analysis of EGC diagnosis demonstrated the superiority of NBI over WLI[103]. Pimentel-Nunes et al[104] found that compared with WLI, NBI has significantly increased the sensitivity of the diagnosis of intestinal metaplasia and dysplasia (87% vs 53% and 92% vs 74%, respectively) while maintaining high specificity (approximately 97%). Sugano et al[105] also confirmed these findings. Blue light imaging (BLI) is an endoscopic imaging technique that involves the absorption of short wavelengths of reflected light by hemoglobin and the mucosa for observation. It can be used for the diagnosis of both superficial microvascular and deep vascular structures. A meta-analysis indicated that the sensitivity of BLI for GC detection was 91.9%, the specificity was 93.4%, and the accuracy was 95.4%[106].

Linked color imaging involves a combination of narrow-band wavelength light and white light to improve the lesion detection rate by enhancing mucosal color contrast. Linked color imaging is significantly superior to WLI in detecting UGI lesions, especially precancerous gastric lesions, with a higher detection rate, sensitivity and specificity[107,108].

Texture and color enhancement imaging (TXI) aims to improve the morphological characterization of subtle surface irregularities and increase the brightness and color variation in dark areas to improve the diagnostic efficiency of EGD. The difference in color between atrophy and intestinal metaplasia under TXI was significantly greater than that under WLI[109]. TXI increases the color variation around areas of atrophy and intestinal metaplasia, thus improving diagnostic efficiency and enhancing the stratification of the GC risk. In the future, the effect of TXI on real-time EGC detection should be evaluated in large-scale prospective studies.

Real-time diagnostic technology, such as confocal laser endomicroscopy (CLE) and endocytoscopy (EC), enables real-time imaging of living tissue cells in the gastrointestinal mucosa during digestive endoscopy, offering the advantage of optical biopsy. CLE uses a low-power laser to illuminate a predetermined tissue plane, and then the optoelectronic detector detects tissue fluorescence focused through a pinhole aperture, converts it into an electronic image using a computer, and finally forms a grayscale image representing a specific plane. At present, CLE can be categorized into two types: Endoscope-based CLE (eCLE) and probe-based CLE (pCLE). In eCLE, CLE is integrated at the front end of the endoscope. In pCLE, the CLE probe needs to pass through the biopsy channel of the conventional endoscope. After many years of development, the classification criteria for CLE have been established based on the gastric crypt pattern and microvascular structure, and the sensitivity and specificity of CLE for predicting tumors are significantly higher than those of white light endoscopy[110]. A meta-analysis showed that CLE achieved up to 88% sensitivity and 98% specificity in diagnosing GMA, and up to 93% sensitivity and 98% specificity for diagnosing gastric intestinal metaplasia. Through a comparison, both eCLE and pCLE have high values for atrophy and gastric intestinal metaplasia; however, the superior flexibility and enhanced image acquisition capabilities of pCLE yield greater diagnostic accuracy than eCLE[111]. Early detection and diagnosis of esophagogastric junction adenocarcinoma using conventional endoscopy or image-enhanced endoscopy remain challenging. An EP-HMRG fluorescent probe has been developed. This probe undergoes enzymatic activation following cleavage at a dipeptidyl peptidase-IV-specific sequence and has been used to detect squamous cell carcinoma in the head and neck region and esophagus[112]. EP-HMRG fluorescence imaging achieved 85.7% sensitivity, specificity, and accuracy for EGC detection[113].

EC is a contact-type endoscope with ultrahigh resolution and magnification. Under EC, the morphology of gastric glands, cellular composition and arrangement within gastric crypts, and nuclear staining intensity can be clearly visualized[114]. A study revealed that the sensitivity, specificity and accuracy of EC in the diagnosis of GC were 88.0%, 92.9% and 90.6%, respectively[114]. However, compared with histological sections, CLE and EC also have many limitations, such as restricted scanning depths and coverage areas, inferior visualization of microscopic structures such as cell nuclei, and the absence of widely validated diagnostic criteria. With the rise of AI and advancements in technologies such as molecular probes, these shortcomings may gradually be overcome, thereby promoting their application in the diagnosis of EGC.

By integrating 22 studies, the overall missed diagnosis rate for GC during endoscopy was estimated to be 9.4%[115], whereas AI-assisted endoscopy can effectively reduce the missed diagnosis rate of gastric lesions[116]. AI-assisted endoscopy technology can be categorized into computer-aided detection, computer-aided diagnosis, and computer-aided quality assessment. Computer-aided detection serves as a diagnostic tool for detecting EGC, enabling the real-time monitoring of its presence. In a binary classification study of benign vs malignant gastric lesions, the AUC of the EffcientNetB7 model was 0.9943, with an accuracy rate of 91.76% for EGC prediction and an accuracy of 99.52% for the prediction of benign lesions[117]. After training the imaging data from more than 10000 patients, the ENDOANGEL-LD system was developed by a Chinese team, and the detection sensitivity and specificity of EGC exceeded 90% in more than 2000 patients[118]. Computer-aided diagnosis plays a qualitative role in the diagnosis of EGC, enabling the prediction of its invasion depth. Gong et al[119] trained a deep learning model on 5017 endoscopic images to predict the depth of invasion of GC, achieving an accuracy rate of 89.2%. The AI-scope system even outperformed EUS in assessing the depth of invasion[87]. Computer-aided quality assessment serves a quality control function, ensuring an adequate examination time and reducing observation omissions in gastric blind spots. Studies have indicated that the EndoAngel system consistently extends the gastric mucosal examination time, reduces blind spot rates during EGD, and reduces the missed detection rate in a serial methodological design[115].

DISCUSSION

GC screening methods include the measurement of serum biomarker levels, H. pylori testing, liquid biopsy, imaging, and endoscopy. To provide an intuitive comparison of the advantages and limitations of different GC screening methods, key metrics are summarized below (Table 1). Among serum biomarkers, tumor markers are more commonly used for monitoring treatment efficacy and the prognosis. Gastric function markers, which are characterized by noninvasiveness, convenience, and a low cost, have become the preferred method for large-scale population screening for GC. They indicate the GC risk by reflecting the status of gastric mucosal function. However, their diagnostic specificity and sensitivity remain limited because of interference from benign gastric diseases. Research has indicated that combining PGI/PGII with G-17 and H. pylori detection effectively identified high-risk populations for GMA. However, its specificity is influenced by factors such as age, diet, and medications, and its sole use may lead to missed diagnoses of EGC. UBT, serving as the “noninvasive gold standard” for H. pylori infection, can reduce the risk of GC by eradicating H. pylori. However, it cannot directly reflect the severity of gastric mucosal lesions and requires combination with other indicators. Japan employs a risk stratification approach that combines H. pylori serological testing with PG testing to optimize screening efficiency. These liquid biopsy biomarkers can compensate for missed endoscopic diagnoses and are suitable for large-scale screening[120].

Table 1 Comparison of gastric cancer screening methods.

Screening methods	Sensitivity	Specificity	Advantages	Limitations
Tumor markers
CA724	33.0%	94.0%	Simple to detect and noninvasive, suitable for monitoring therapeutic efficacy and prognostic assessments	Low sensitivity and specificity, high false-positive rate, not suitable for early screening
CEA	25.5%	97.9%
CA125	31.1%	97.3%
CA199	38.7%	92.6%
Gastric function biomarkers
PG	57%-59%	73%-87%	Noninvasive, convenient, low-cost	Sensitivity and specificity are limited due to interference from benign gastric conditions
G-17	70%	93%
GastroPanel	51%-59%	61%-66%	Noninvasive and convenient; aids in diagnosing gastric mucosal diseases	Low sensitivity and specificity; threshold optimization requires a consideration of baseline population characteristics
Liquid biopsy
CTCs	85.3%	90.3%	High tumor specificity; noninvasive; aids in early diagnosis and prognostic assessments	Enrichment and identification techniques lack uniform standards; low blood levels; prone to interference from epithelial-mesenchymal transition processes or benign inflammation
CtDNA	51.5%	99.5%	Noninvasive with high patient compliance; predicts postoperative recurrence	Low sensitivity; lack of standardized operating procedures
DNA methylation	56%-63%	91%-100%	Noninvasive; high specificity; combined testing increases detection efficacy	Testing techniques need standardization; testing costs remain relatively high; multicenter studies are needed for validation
MiRNA	87.0%	68.4%	Good serum stability, high diagnostic accuracy	Research heterogeneity and inconsistent results; high costs
LncRNAs	80%	70%	Predict tumor invasion/metastasis/prognosis; their combination with protein markers increases diagnostic efficacy	The specificity of standalone testing is limited, and further research is needed to validate their clinical utility
CircRNAs	78%	84%	Noninvasive; high stability; early diagnosis	Detection technology requires standardization; clinical implementation data are insufficient
Imaging examinations
Gastric ultrasound	60.8%-88.7%	83.5%-91%	Noninvasive, radiation-free; clearly displays gastric wall layers, supplements T staging	EGC detection has low sensitivity; it is significantly affected by gastric gas and operator technique; biopsy is not feasible
Upper gastrointestinal series	36.7%	96.1%	Dynamic observation of gastrointestinal motility; relatively simple to operate	Radioactive, biopsy cannot be performed; low sensitivity; high false-negative rate
CT	77.1%-88.9%	80.0%-96.8%	Assesses the depth of invasion and metastasis	Limited sensitivity in detecting EGC; radiation exposure; requires large-scale prospective validation
MRI	71.4%-82.6%	91.4%-100%	High soft tissue resolution with no radiation exposure; diffusion-weighted imaging demonstrates high accuracy in detecting lymph node metastasis	The examination is time-consuming, with insufficient sensitivity for detecting early mucosal lesions; biopsy is not feasible
Endoscopic examinations
EUS	50%-90%	NA	Accurately determines the depth of invasion and peri-gastric lymph nodes; guides endoscopic resection	High technical demands and time-consuming; biopsy is not feasible; low accuracy in T2 lesion assessments
MCCE	92%	90%	Noninvasive, no anesthesia needed; excellent tolerability; capable of detecting lesions missed by gastroscopy	Unsuitable for biopsy/treatment; difficult to control through the pylorus; relies on gastrointestinal motility
EGD	74.6%	94.0%	Intuitive visualization and precise localization; high diagnostic accuracy; biopsy confirmation	Invasive, low compliance; potential risk of complications; high cost

CA: Carbohydrate antigens; CEA: Carcinoembryonic antigen; PG: Pepsinogen; G-17: Gastrin-17; CTC: Circulating tumor cell; ctDNA: Circulating tumor DNA; miRNA: MicroRNA; lncRNA: Long noncoding RNA; circRNA: Circular RNA; CT: Computed tomography; MRI: Magnetic resonance imaging; EUS: Endoscopic ultrasonography; MCCE: Magnetically controlled capsule endoscopy; EGD: Esophagogastroduodenoscopy; EGC: Early gastric cancer; NA: Not available.

Enhanced abdominal and pelvic CT is the preferred imaging modality for GC. MRI serves as an alternative when contrast-enhanced CT is contraindicated or when liver metastasis is suspected. It aids in detecting early liver metastases and assessing the extent of invasion in advanced cancer, thereby improving the accuracy of T staging. Positron emission tomography/CT can assist in evaluating distant metastases and is indicated for patients where treatment decisions are influenced by findings that cannot be accurately determined by conventional imaging. Barium contrast studies are primarily recommended for cancers at the gastroesophageal junction to assess the extent of esophageal invasion and determine the Siewert classification.

EGD remains the gold standard for EGC screening. EGD has greater advantages in the early detection of GC (particularly early-stage lesions), whereas the sensitivity of the UGI series is lower (36.7% vs 69.0%)[97]. Compared with UGI, EGD has a slightly higher per-procedure cost but offers greater overall cost-effectiveness because of its higher sensitivity and lower screening frequency. However, a RCT conducted in Akita Prefecture, Japan, revealed that annual barium meal examinations followed by endoscopy for abnormal findings yielded greater economic benefits than endoscopy after ABC risk stratification based on mobile endoscopy[121]. Iterative upgrades of CE have addressed the invasive drawbacks of endoscopy. However, it has several limitations, such as the inability to perform immediate biopsies, difficulty in locating lesions, and relatively high costs. Currently, it serves only as a supplementary screening method.

The results of the cost-effectiveness analysis indicate that screening is generally more cost effective than no screening. Among screening methods, endoscopy is more cost effective than UGI is but is not more effective than H. pylori screening, PG testing, or novel risk scoring approaches. However, a meta-analysis suggested that endoscopic screening was cost-effective in moderate-risk settings, particularly when combined with colorectal cancer screening[122]. H. pylori screening is more cost-effective than endoscopy and symptomatic treatment, but it is not superior to serum PG testing or risk scoring methods. H. pylori screening based on UBT is more cost-effective than most alternative approaches[123]. In regions with an incidence rate ≥ 4.2 per 100000, the screening and eradication of H. pylori were cost-effective, with data from Japan and China supporting its feasibility[124]. European guidelines indicate that population-based H. pylori screening and treatment are cost-effective in populations at high risk of GC and that GC prevention screening combined with colorectal cancer screening represents a potential screening opportunity. Serum markers such as miRNAs and PG have shown significant potential in risk stratification. For instance, the ICER for miRNA screening is 40971 dollars per quality-adjusted life year, which falls within the cost-effective range[125]. Regarding screening strategies, in high-prevalence regions such as Japan and South Korea, endoscopic screening every 2-3 years is standard practice, although H. pylori testing is more cost-effective. In low-prevalence areas such as the United States and Europe, noninvasive methods are more widely recommended to reduce unnecessary endoscopic burdens.

For resource-constrained regions, a tiered screening strategy based on risk stratification can significantly reduce resource consumption while maintaining high detection efficiency. For instance, in certain pilot programs, risk models constructed using readily accessible indicators such as H. pylori infection status and family history reduced endoscopy volumes by 37.9% without compromising early cancer detection rates[126]. In resource-constrained regions, limited resources should be prioritized for managing high-risk populations rather than universal screening, thereby maximizing public health benefits. In the future, localized approaches tailored to regions with varying economic capacities should be explored to advance equity in global GC prevention and control.

Despite numerous breakthroughs in EGC screening research, several bottlenecks remain to be addressed in clinical application. First, screening technologies have yet to achieve an effective balance between accuracy, cost, and patient comfort: While novel endoscopic techniques offer high precision, their expensive equipment and complex operation hinder their widespread adoption in primary healthcare facilities; serological screening, although low cost, suffers from insufficient specificity. CE is comfortable and noninvasive but cannot perform immediate biopsies. Second, screening and intervention for precancerous lesions remain weak: The progression of precancerous conditions such as GMA and intestinal metaplasia is a long-term reversible process, yet no unified intervention protocol exists. Furthermore, the screening sensitivity for some precancerous lesions is low, increasing the risk of missing optimal intervention windows. Third, population screening compliance remains low: Due to the absence of obvious clinical symptoms of EGC, some individuals underestimate the importance of screening. Combined with the invasiveness of certain screening methods and cumbersome screening procedures, screening coverage is insufficient among high-risk populations, particularly populations residing in rural and remote areas where population screening rates urgently need improvement. Fourth, unified guidelines and quality control standards for EGC screening are lacking. The screening strategies used vary across countries and regions, and the technical proficiency of primary healthcare institutions is inconsistent, resulting in poor comparability of screening outcomes and hindering nationwide data interoperability and standardized management of screening programs.

CONCLUSION

GC, a major global health threat, has a prognosis that is highly dependent on early diagnosis, with early screening being the core breakthrough for improving patient survival. This review shows that GC development results from the synergistic effects of multiple factors, with H. pylori infection being the most clearly established class I carcinogen. However, a comprehensive risk assessment must incorporate dietary habits, genetic predispositions, and lifestyle factors.

Regarding screening technologies, endoscopy remains the gold standard for GC diagnosis. Its integration with image enhancement techniques such as NBI and BLI, along with AI-assisted diagnostic systems, significantly increases the detection rate of early lesions. Serum gastric PG and G-17 biomarker testing, leveraging noninvasive and low-cost advantages, are suitable for large-scale population screening. Liquid biopsy technologies such as ctDNA and CTCs demonstrate promising development potential, offering new pathways for noninvasive dynamic monitoring. Imaging examinations play a crucial supplementary role in tumor staging.

In summary, this study confirms significant regional disparities in GC incidence. East Asia prioritizes early screening to reduce mortality, while Western regions focus on high-risk management due to resource constraints. AI technologies can narrow these gaps by optimizing endoscopic diagnostic efficiency; however, risk-stratified stepwise screening remains a viable approach for low-resource areas. To further improve precision screening for GC, it is recommended to prioritize H. pylori infection as primary prevention tool among high-risk populations. Additionally, in regions with a high GC incidence, serum PG combined with H. pylori testing should be promoted alongside endoscopic examination as a screening strategy for GC.

This review aims to provide an evidence-based references for clinicians in selecting screening strategies and to highlight research directions for developing more efficient and accessible screening tools in the future. With the continued advancement of GC screening technologies in the future, we anticipate that the early detection rate of GC will significantly improve, mortality rates will decrease, the patient prognosis will improve, and the global burden of GC will decrease.