In spite of declining incidence in recent years, gastric cancer is still one of the most frequently occurring cancers. The most recent estimates from the International Agency for Research on Cancer (IARC) GLOBOCAN 2012 indicate that nearly one million new gastric cancer cases and more than 700,000 deaths occurred globally in 2012.1 The disease accounted for 7% of the total new cancer cases and 9% of the total cancer deaths. Gastric cancer is now the fifth most common cancer in the world, after lung, breast, colorectal and prostate cancer and the third leading cause of cancer death.1 There is a 10-fold variation in gastric cancer incidence internationally, with high rates seen in many countries of Eastern Asia (age standardized rate, 42.4/100,000 in 2008), Central and Eastern Europe (21.9/100,000), and Central (12.7/100,000) and South America (17.3/100,000), and much lower rates reported from North America (5.8/100,000), and Africa (4.7/100,000) (Fig. 1). In addition, rates in men are approximately double those observed in women.1,2

Over the past four decades, the age-standardized incidence as well as mortality rates from gastric cancer have steadily declined in nearly all populations, independently from their background risk of gastric cancer or sex (Fig. 2).3 Allowing for the estimated annual percentage change of -2%, the annual number of new gastric cancer cases (both sexes) would still slightly increase or remain stable in the year 2030 due to ageing of the population.1,4 The relative 5-year survival rates for gastric cancer are low in most countries with less than 30% except for the Republic of Korea and Japan with around 70% where screening programmes that lead to early detection are in place. The case fatality rate is lower in countries with high levels of human development (overall mortality-to-incidence ratio=0.65) than in countries at low or medium levels of human development (0.83).2

Currently, the incidence rates of gastric cancer among men in the Republic of Korea is the highest in the world.4 It has been estimated that the age-standardized rates were 63.3 in men and 25.1 per 100,000 in women, respectively, with approximately 32,000 new gastric cases being diagnosed in 2011.5 The rates have remained stable for many years (67.2 in 2001 and 63.3 in 2011 for men; 26.2 in 2001 and 25.1 in 2011 for women) without geographical variation across the country.6 Gastric cancer was the most frequently occurring cancer in men, accounting for 19.6% of all cases and the third most frequently diagnosed cancer in women, accounting for 10.3% of all cases occurred in Koreans in 2012.7 Recent mortality data in Korea showed that gastric cancer was the third leading cause of cancer death in men, and the second leading cause of cancer death in women.5 The mortality rate for gastric cancer has decreased continuously both in men and women since 1997. The 5-year survival rate for gastric cancer in Korea have been much improved over the last two decades, showing an increase from 43% in 1993 to 1995 to 67% in 2006 to 2010.7

Gastric cancer represents a biologically and genetically heterogeneous group of tumours with multifactorial aetiologies, both environmental and genetic.2,8 Gastric cancers arising from the most proximal (cardia) or distal (non-cardia) region are likely to have different aetiologies. The majority of gastric cancers are noncardia cancers, while cardia cancers have been most commonly reported in North American and European populations.2

In most cases of noncardia gastric cancer, the cancer develops from the epithelial cells of the gastric mucosa with a transition from dysplasia to confirmed cancer. The successive steps in the sequence of gastric carcinogenesis, in relation to Helicobacter pylori infection of the mucosa, have been described by Correa.9 Those steps include: (1) chronic atrophic gastritis of the mucosa up to the lamina propria by the inflammation preceded by H. pylori bacterial infection; (2) intestinal metaplasia in large areas of the epithelium; (3) premalignant adenomatous lesion with succession of low and high grade dysplasia; and (4) intramucosal cancer.

Only a very small proportion of gastric cancer cases is linked to germline mutation in E-cadherin/CDH1, which has been found in approximately 25% to 40% of families with hereditary diffuse gastric cancer.27,28 The penetrance of CDH1 gene mutations is high, with an estimated risk of >80% by the age of 80 years with poor prognosis and late presentation with a highly invasive diffuse type tumour.29

Two major autosomal dominant forms of heritable colorectal cancer, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer (Lynch syndrome), are also linked to increased risk of other cancers including gastric cancer. Lynch syndrome is caused by germline mutations in four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2), resulting in development of a spectrum of different tumours and Lynch syndrome mutation carriers have shown a substantial risk for developing gastric cancer.30 The risk of gastric cancer is also increased in Li-Fraumeni syndrome with germline mutation of TP53.31

Peutz-Jeghers syndrome is an inherited multiple gastrointestinal polyposis associated with mucocutaneous pigmentation.32 Germline mutation in the LKB1 gene that encodes serine/threonine-protein kinase that acts as a tumour suppressor results in the loss of LKB1 function which can lead to gastric cancer carcinogenesis.33

While hereditary gastric cancer is uncommon, genetic alterations in sporadic gastric cancer cases are frequently reported. However, no major high-penetrance genes have been discovered so far,29 although genetic factors might play an important role in gastric carcinogenesis by possibly influencing immune and inflammatory responses especially to H. pylori infection and thereby altering susceptibility to gastric cancer.34

Polymorphisms of the interleukin 1β gene (IL-1β), which contributes to initiation and amplification of inflammatory response, and of the interleukin-1 receptor antagonist (IL-1RN) gene, which modulates inflammation, have been associated with gastric cancer risk. However, a systematic review of 35 studies did not find an overall association of polymorphisms in these inflammatory genes with risk of gastric cancer, but there was significant heterogeneity among study results.35 Results from very large genome-wide association studies (GWAS) showed reproducible associations between single-nucleotide polymorphisms located at prostate stem cell antigen gene (PSCA), PLCE1, and Mucin 1, cell surface-associated gene (MUC1) genes and different subtypes of gastric cancer risk. These results from GWAS are mainly from Chinese, Korean and Japanese populations and the clear biological mechanism behind these polymorphisms is not yet clearly known.29

The main cause of gastric cancer is chronic infection with H. pylori.36,37 The IARC classified H. pylori as a class I carcinogen in 1994 and reconfirmed this classification in 2009 after reviewing newer evidence.38 According to the most recent estimates using a more sensitive method to detect H. pylori, approximately 89% (770,000 cases) of distal gastric cancer cases worldwide have been estimated to be attributable to chronic H. pylori infection.39 H. pylori infection is present throughout the world and causes most cases of peptic ulcer disease and mucosa-associated lymphoid tissue lymphoma, as well as gastric cancer. The prevalence of infection in adults varies between 20% to 50% in industrialized countries and over 80% in many developing countries.40 H. pylori infection is strongly associated with socioeconomic conditions,41 and transmission appears to occur through close personal contact, particularly within the family38 and typically in early childhood. Once established, infection usually persists throughout life unless treated. The prevalence of H. pylori infection has decreased in recent decades, particularly among children in developed countries, probably reflecting improvements in hygiene.42,43 However, there is only limited information on prevalence trends among children from most countries,41,44 and H. pylori still infects an estimated 50% of the world's population.

Factors associated with colonization and pathogenicity of H. pylori include virulence factors like cytotoxin-associated gene A (cagA) in the cag pathogenicity island and the vacuolating cytotoxin A (vacA). cagA is a gene that is part of the cag pathogenicity island and colonization with strains that possess cagA is associated with increased risk of developing both intense tissue responses and premalignant and malignant lesions in the distal stomach through secreting a functional cytotoxin which induces more severe gastric injury and further augment the risk.45,46 CagA has been shown to associate with the apoptosis-stimulating protein of p53, inhibiting the apoptotic function of p53, in a manner similar to human papillomavirus (HPV) and other oncogenic DNA viruses.47 vacA encodes a secreted bacterial toxin (VacA) and induces multiple structural and functional alterations in cells, the most prominent of which is the formation of large intracellular vacuoles.48 Primarily due to variations in vacA gene structure, vacA positive strains vary considerably in production of cytotoxin activity, despite its universal presence in all H. pylori strains examined.45

Another infectious agent that has been associated with gastric cancer is the Epstein-Barr virus (EBV). The virus is a ubiquitous infectious agent with a prevalence of over 90% in adults and has been causally linked to the development of several malignancies, including Burkitt's lymphoma, immunosuppression-related lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma.49 Approximately 8% of gastric cancers have been estimated to harbour EBV,50 but there is insufficient epidemiological evidence of a clear etiological role for EBV in gastric carcinogenesis.38 The EBV genome is present in the tumour cell in a monoclonal form, and transforming EBV proteins are expressed in the tumour cell. A meta-analysis reported that the prevalence of EBV-positivity in gastric cancer varied jointly by age, sex and anatomic subsite, i.e., EBV-positivity decreased with age among men, more steeply for tumours localised to the antrum.50 In addition, EBV-positivity has been associated with longer survival,51 suggesting that EBV-positive gastric cancer may have distinct clinical and genetic features, and therefore may be a separate clinical entity.

Various other risk factors including older age, male sex, cigarette smoking, low socioeconomic status, low level of physical activity, and radiation exposure have been linked to increased risk of gastric cancer in general while gastroesophageal reflux disease and obesity have been associated with increased risk of gastric cardia cancer specifically.29 Nonsteroidal anti-inflammatory drugs and statin intake have shown inverse associations with gastric cancer risk.29

Dietary factors have been investigated in many studies in relation to gastric cancer risk, since food carcinogens can potentially interact directly with the epithelial cells that line the stomach. A comprehensive systematic review of dietary factors and cancer prevention published by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) concluded that nonstarchy vegetables, including specifically allium vegetables, as well as fruits probably protect against gastric cancer while salt, and also salt-preserved foods, are probably causes of this cancer.52 A high concentration of sodium chloride has been shown to cause damage to the gastric mucosa, cell death and consequent regenerative cell proliferation in animal models,53,54 which may lead to inflammation and damage such as diffuse erosion and degeneration.55 Studies have found that a high salt diet was associated with colonization of H. pylori56 and exacerbated H. pylori-induced inflammation,57 which in consequence was responsible for promotion of gastric carcinogenesis in a dose-dependent fashion.58 This was also confirmed in other studies showing that salt worked synergistically with H. pylori infection to enhance the expression of proinflammatory enzymes and cytokines such as inducible nitric oxide synthase and cyclooxygenase-2 in the gastric mucosa.59 In addition, high salt concentrations have been shown to stimulate increased expression of H. pylori CagA, which in turn leads to an increased amount of CagA translocated into gastric epithelial cells and an enhanced ability of H. pylori to alter gastric epithelial cell function.60

Another dietary factor that might play a role in gastric carcinogenesis is N-nitroso compounds.52 Nitrates, produced endogenously in gastric acid, and added as preservatives to processed meats may contribute to N-nitroso compound production and exposure that are suspected mutagens and carcinogens.52 Previous studies have shown a significant increase of gastrointestinal cancer risk associated with dietary61 or endogenous exposure to N-nitroso compounds,62 especially with noncardia gastric cancer rather than cardia gastric cancer.62 Many processed meats contain high levels of salt and nitrite. Haem found in red meat promotes the formation of N-nitroso compounds through direct reaction between nitric oxide and haemoglobin and myoglobin.61 Red meat also contains iron, which can lead to the production of free radicals. Vitamin C may be protective against H. pylori-associated gastric carcinogenesis by enhancing mucosal immune response, neutralizing free radicals, reducing the formation of gastric N-nitroso compounds, inhibiting cell proliferation and directly affecting H. pylori growth.62 The gastric juice vitamin C levels were also shown to be lower with infection with CagA positive H. pylori strains compared with CagA negative H. pylori strains.63,64 Even with the biologically plausible mechanisms, epidemiological evidence suggesting that dietary nitrate and nitrite or other N-nitroso compounds are the causes of gastric cancer is limited. The WCRF/AICR report assessed other dietary factors and concluded that the available evidence suggesting that pulses (legumes) and foods containing selenium protect against gastric cancer and that chilli, processed meat, smoked foods, and grilled (broiled) and barbecued (charbroiled) animal foods are causes of stomach cancer is also limited.52

The two major primary prevention strategies for gastric cancer at a population level might include improvement in diet and reduction in the prevalence of H. pylori, the main cause of gastric cancer.2 Prevention through dietary intervention would be with increased fruit and vegetable intakes and decreased consumption of salt or salt-preserved foods. Lifestyle modification such as increased physical activity and smoking cessation may also help reduce risk of getting the disease. Interventions for primary prevention at the population level may potentially involve very large numbers of people that require convincing evidence of effectiveness. However, interventions based on these dietary strategies have not yet been evaluated in large-scale randomized clinical trials examining their impact on gastric cancer incidence or mortality.

Another strategy to prevent gastric cancer would be through H. pylori eradication. Recognition of the causal role of chronic H. pylori infection in gastric cancer led some authors by 2005 to call for broad-scale programmes to eradicate the infection as a way to prevent the disease.65 However, no countries with high burden of gastric cancer have yet implemented a population-based H. pylori eradication programme. Some of this inaction may reflect doubts about the effectiveness of H. pylori eradication in preventing gastric cancer as there are still scant data available from randomized clinical trials.66,67 Recently, a new meta-analysis of all six reported randomized trials among asymptomatic adults estimated a benefit (relative risk=0.66, 95% confidence interval [CI], 0.46 to 0.95).68 In 2012, a trial in a general population of adults in China reported a statistically significant reduction in gastric cancer risk following treatment after 15 years of follow-up (4.6% in control group, 3.0% in treated group; odds ratio, 0.61; 95% CI, 0.38 to 0.96).69 Two trials have assessed the effect of H. pylori treatment after endoscopic mucosal resection of early gastric cancer.70,71 One of the trials, in Japan, reported a statistically significant reduction in risk of metachronous gastric cancer.71 Risk also appeared lower in a study conducted in the Republic of Korea, but the result was not statistically significant.70 Although these results of randomized trials indicate that H. pylori treatment may lower gastric cancer incidence by 30% to 40%, there are important limitations to the available data. Firstly, the meta-analysis finding is based on relatively few trials, many of which had too few cancer endpoints to contribute much weight to the analyses. Secondly, because of the relative paucity of endpoint data, the estimated size of the overall beneficial effect of treatment is likely to be imprecise. Thirdly, the larger trials were all conducted among middle-aged adults in Asia, notably in China, and the generalizability of their results to other populations is not certain. Lastly, the trials do not provide direct data on the feasibility, costs, effectiveness, and adverse effects of treatment programmes as they are applied in community settings.72

A recently published report of a working group of the IARC of the WHO concluded that-randomized clinical trials have found that H. pylori treatment is effective in preventing gastric cancer, and models indicate that H. pylori screening and treatment strategies would be cost-effective. However, uncertainties remain about the generalizability of results and about the cost-effectiveness and possible adverse consequences of programmes applied in community settings. The Working Group therefore recommends that countries explore the possibility of introducing population-based H. pylori screening and treatment programmes, but cautions that decisions as to whether and how to implement H. pylori testing and treatment must hinge on local considerations of disease burden, other health priorities, and cost-effectiveness analyses. Moreover, these programmes should be implemented in conjunction with a scientifically valid assessment of programme processes, feasibility, effectiveness, and possible adverse consequences."73,74

Gastric cancer remains the third leading cause of cancer death worldwide and the burden of disease, which for unknown reasons affects twice more men than women and varies widely from place to place, is expected to remain high for many decades despite declining trends. The disease is usually detected late and survival is poor in most settings. With few exceptions, there are no public health programmes aimed at reducing gastric cancer burden.

Primary prevention interventions, including dietary modifications and eradication of H. pylori need to be considered as potentially valuable tools in the control of this disease. H. pylori can be treated with antibiotics and in clinical trials, its eradication has been shown to reduce gastric cancer incidence between 30% and 40%. However, given the high prevalence of infection in high risk areas and limited information about feasibility, acceptability and potential adverse consequences of the intervention, it has not been broadly implemented. Several trials are underway that should provide additional data, but demonstrations projects with proper evaluation of the programme were recently recommended by an IARC working group of international experts.

More rapid impact on the burden of disease might be forthcoming from secondary prevention through early detection and prompt treatment of precursor lesions and early cancer. Encouraging progress has been achieved in Japan where opportunistic screening is widespread, and in the Republic of Korea where screening is conducted in an organized programme. However, the methods used in these countries require infrastructure and human resources with ample expertise which are not available in less developed areas. In addition, the effectiveness of the screening methods has not been validated in randomized controlled clinical trials.

Endoscopic detection and treatment is only one important facet of the complex process of gastric cancer screening. To achieve an appropriate benefit, screening should only be considered in regions with a significant burden of disease.97,98,99 In addition, screening should be conducted in organized, population-based programmes to promote equal access through personal invitation and to facilitate comprehensive quality assurance systems. Before gastric cancer screening can be recommended as a public health policy in other countries, information is required on expected detection rates, participation rates, acceptability, economic costs, as well as any complications or adverse effects associated with screening in different populations. The highly successfully organized screening programme in the Republic of Korea provides a unique opportunity to conduct population-based studies within the framework of the programme. This will not only help maintain and further improve the quality of the programme, but also provide valuable evidence for other countries considering the potential of gastric cancer screening to reduce the burden of disease in their populations.