Adenocarcinoma of the Stomach and Other Gastric Tumors

Hp Infection (see also Chapter 52 )

Hp is a gram-negative microaerophilic bacterium that infects nearly half the world’s population and is recognized as the primary etiologic agent for gastric cancer. Indeed, H. plyori has been classified as a class I (or definite) carcinogen by the International Agency for Research on Cancer, a branch of the WHO. Infection with Hp has been found in every population studied, although the prevalence is higher in developing countries and most parts of East Asia. ^,

The natural history of chronic Hp infection includes 3 possible outcomes : (1) simple gastritis, where patients often remain asymptomatic; (2) duodenal ulcer phenotype, which occurs in 10% to 15% of infected subjects; and (3) gastric ulcer/gastric cancer phenotype. The risk for gastric cancer development varies with the type of background gastritis, but in general, corpus-dominant gastritis resulting in a low acid state is mainly associated with an increased risk. Hp -induced duodenal ulcer disease is associated with a high gastric acid output as well as a reduced risk for developing gastric cancer. Studies suggest that Hp -infected patients develop chronic atrophic gastritis at a rate of 1% to 3% per year of infection. ^{, ,} Thus, those patients who are genetically predisposed to developing atrophic gastritis in response to Hp infection are likely to be also predisposed to gastric cancer. Although Hp infection is associated with both diffuse-type and intestinal-type adenocarcinomas, we focus in this chapter mainly on the mechanisms responsible for the formation of intestinal-type adenocarcinoma because they have been better studied. The association of Hp with mucosa-associated lymphoid tissue lymphoma is discussed in Chapter 32 .

The increased risk of development of gastric adenocarcinoma due to Hp infection depends on multiple factors including host genetic factors, the strain of bacteria (including bacterial virulence factors), the duration of infection, and the presence or absence of other environmental risk factors (e.g., poor diet, smoking). In a Japanese cohort, only those infected with Hp developed gastric adenocarcinoma during follow-up (2.9% vs. 0%; P <0.001). Additional cohort studies from China and Taiwan have reported similar findings. ^, In Western countries, the association between Hp and gastric cancer appears to be confined to nonjunctional tumors. There are data, however, that Hp is likely to be also associated with Siewert type III junctional cancers as well as potentially a subgroup of type II tumors. ^,

A combination of a virulent bacterial strain, a genetically permissive host, and a favorable gastric environment may be necessary for cancer to occur. Currently, genetic susceptibility factors of the human host are studied based on individual genes, but new technologies such as next-generation sequencing will enhance the identification of host genetic factors. Nevertheless, the most important factor appears to be the induction of chronic inflammation by Hp infection. This leads to an impairment of the epithelial barrier function of the gastric mucosa, thereby increasing the impact of other pathogenic factors (e.g., diet). Several aspects of the inflammatory milieu have been implicated as carcinogens; they include increased oxidative stress and the formation of oxygen free radicals, leading to DNA damage, increased CD4+ T cells and myeloid cells, and elevated proinflammatory cytokine production, all leading to accelerated cell turnover, reduced apoptosis, and the potential for faulty or incomplete DNA repair. Indeed, recent studies suggest that animals with deficient DNA repair mechanisms display more severe gastric dysplasia after chronic infection with Hp . As mentioned earlier, Hp is capable of directly modifying DDR-related genes and their function. Thus, evidence to date clearly indicates that the most important cofactor in the induction of Helicobacter -related disease is the host immune response. Indeed, chronic inflammation has been linked to a large number of nongastric cancers.

Chronic inflammation of the gastric mucosa appears necessary for the progression through atrophy to gastric cancer. Disease mechanisms are difficult to study in human infection, and therefore, much of our understanding of the immune response to Helicobacter organisms comes from work performed in a mouse model. Different inbred strains of mice respond to infection with varying degrees of disease susceptibility, and several knockout models have helped to elucidate the roles of individual components of the immune response in disease.

Genetic manipulation of the C57BL/6 susceptible murine strain has facilitated detailed study and has thus led to a deeper understanding of genetic factors that promote murine gastric cancer, and particularly, the role of the adaptive immune response. For example, gastric Helicobacter infection in mice deficient in lymphocytes does not result in tissue damage, cell lineage alterations, or the metaplasia-dysplasia-carcinoma sequence. ^, In contrast, infection in B cell-deficient mice (which retain a normal T cell response) results in severe atrophy and metaplasia identical to that seen in infected wild-type mice. Taken together, these studies underscore the crucial role of CD4+ T lymphocytes in orchestrating gastric neoplasia.

Susceptible mouse strains, such as C57BL/6, mount a strong Th1 (T helper cell type 1, expressing interferon [IFN]-γ and interleukin [IL]-12) type of immune response, whereas resistant strains, such as the BALB/c, have a polarized Th2 response (expressing IL-4 and IL-5). A Th2 response is associated with protection from mucosal damage despite the inability to eliminate bacterial colonization and, in fact, is often associated with higher bacterial colonization rates. Mouse strains such as the C3H, which has a mixed Th1/Th2 cytokine profile, show intermediate disease, suggesting that cytokines within an immune response interact to form a continuum of disease rather than discrete disease states. More recently, Th17 cells (expressing IL-17), have been shown to be an important component of Hp -induced gastritis.

Although the composite immune milieu most likely dictates disease manifestations, there may be a role for individual cytokines in both the predisposition to and protection from disease. During Helicobacter infection, the Th1 cytokine IFN-γ can promote or inhibit inflammation-driven cancer of the stomach, suggesting that a more specific immune response is responsible for cancer promotion or surveillance. Although studies in the past have suggested that IFN-γ might promote the development of gastric preneoplasia, IFN-γ overexpression in the stomach at low levels was recently shown to be able to suppress gastric cancer in models of IL-1β– and Helicobacter felis –dependent carcinogenesis. In addition, IFN-γ was shown to counteract the development of Th17 cells. Thus, different composition of the same cells and cytokines in the tumor microenvironment can contribute to a constellation that favors or inhibits carcinogenesis. On the other hand, mice lacking IL-10, a cytokine that acts to dampen an immune response, demonstrate severe atrophic gastritis in response to infection. More recently, genetic murine models have illustrated the importance of the IL-6/IL-11 family of cytokines in the development of gastric cancer.

Manipulation of the immune response within wild-type strains confirms the central role of the Th1/Th2 response in producing disease. For example, infection with the intestinal helminth Heligmosomoides polygyrus skews the immune response toward Th2 polarization and protects the C57BL/6 host from Helicobacter -induced atrophy and metaplasia. This mouse model mimics both the parasitic infection status and the paradoxical low gastric cancer-high Hp infection rates seen in areas of Africa, potentially explaining this apparent inconsistency. These observations in mice led to human studies in Africa and Latin America that confirmed that geographic regions with low gastric cancer rates had much higher Th2/Th1 immune responses to Hp . ^, In general, the increased Th2 type responses were found in areas where serum IgE levels were high and the prevalence of intestinal parasitism by helminthes is above 50%. These findings further stress the importance of the host response to infection and suggest the possibility that manipulation of the genetically predetermined host cytokine profile in response to environmental challenges may lessen or exacerbate the disease process.

Studies on human tissue have also demonstrated that the degree of colonization with Hp depends on various factors, such as the presence and activity of regulatory T-cells (Treg) or the initial (naive) parietal cell mass (which reflects the acid-secreting capacity of the gastric body). Tregs are associated with increasing bacterial colonization, chronic inflammatory changes, and the expression of immunosuppressive cytokines like IL10, IL17, and TGF-β. ^, In case of gastric cancer, Tregs are increased both in the gastric mucosa and the peripheral blood. The ratio of Th1/Th2-derived cytokines is the highest in asymptomatic gastritis, showing a steady decrease in gastric atrophy, intestinal metaplasia and intraepithelial neoplasia progression to gastric adenocarcinoma. This is associated with a concomitant increase of the Treg cell compartment in the peripheral blood as well as persistence of CagA positive strains that favors a Treg-mediated chronic inflammation. Whereas Hp infection has been unequivocally linked to gastric cancer, the development of dysplasia and invasive cancer tends to occur at a time when Hp colonization has either dramatically declined or, in some cases, has disappeared from the stomach altogether. Gastric cancer almost always occurs in the setting of prolonged gastric atrophy and hypochlorhydria, a condition that predisposes to enteric bacterial overgrowth. Although antibiotic eradication therapy targeting Hp delays and inhibits development of gastric cancer in mice, ^, antibiotics eradicate not only Hp but also other microorganisms that colonize the atrophic, hypochlorhydric stomach. Indeed, infection of otherwise germ-free INS-GAS mice with Hp resulted in delayed progression to gastric cancer compared to Hp -infected INS-GAS mice colonized with conventional flora. Thus, Hp may represent simply the initial, or the most prevalent, microbial factor responsible for gastric cancer progression. Ferreira et al. reported recently that the gastric microbiota of patients with gastric adenocarcinomas is significantly different from patients with chronic gastritis. The dominant gastric dysbiosis is characterized by reduced microbial diversity and reduced Hp abundance as well as an overrepresentation of bacterial genera that include intestinal commensals. With regard to these findings, it is also of interest that Hp —when present—dominates the otherwise much more diverse gastric microbiome in humans, as well as mice, prior to cancer development.

There is a great deal of genetic diversity between strains of Hp owing to point mutations, insertions, deletions, and base-pair substitutions within the genome. Several strains may infect a single individual, and existing strains can undergo mutations and change over time. ^, Despite this genetic diversity, several genes are recognized as risk factors for gastric carcinoma, including the cag pathogenicity island, the vacA gene, and the babA2 gene, being the most relevant and most extensively studied thus far among other factors.

The Hp genome is 1.65 million base pairs and codes for approximately 1500 genes, two thirds of which have been assigned biological roles. The function of the remaining one third of the genome remains obscure, but genome-wide analyses using DNA microarray or whole-genome sequencing technology will give a broad view of the genome of Hp in the near future. Factors that contribute to carcinogenesis include those that enable the bacteria to effectively colonize the gastric mucosa, those that incite a more aggressive host immune response, and those that affect host cell-growth signaling pathways.

Motility toward epithelial cells of the stomach is a vital feature of Hp survival tactics. This is ensured by several factors. Spiraling movement is mediated by the FlaA and FlaB proteins, which are designed to navigate the thick gastric mucus. Additionally, Hp produces HP 1069, a putative collagenase, which modifies the extracellular matrix and mucus layer, thus decreasing viscosity and allowing bacterial penetration. ^, In addition, Hp expresses a variety of genes that contribute to buffering of stomach acid in order to maintain a relatively neutral pH. This includes a urease gene cluster consisting of 7 genes, of which UreA/UreB complex (comprising the urease enzyme) codes for 10% of the protein of Hp and is vital for its survival.

The cag pathogenicity island is approximately 40 kb and contains 31 genes. The terminal gene of this island, cagA , is often used as a marker for the entire cag locus. Compared with cagA-negative (cagA−) strains, cag-positive (cagA+) strains are associated with more severe inflammation, higher degrees of atrophy, and a greater chance of progressing to gastric adenocarcinoma. The estimated relative risk has ranged from 2 to as high as 28.4. However, many of the genes adjacent to cagA code for a type 4 secretion system (TFSS), often viewed as a molecule needle that injects bacterial proteins (e.g., cagA) into host cells. The remarkable finding that CagA is injected into host cells, where it is phosphorylated by Src- and c-Abl kinases, has raised the possibility that CagA could directly promote growth, migration, and transformation. Indeed, transgenic expression of Hp CagA induces both GI and hematopoietic neoplasms in mice. Other genes within the pathogenicity island are also believed to be important for disease ( cagE or picB, cagG, cagH, cagI, cagL, cagM ) because they appear to be required for in vitro epithelial cell cytokine release, although they do not seem to have as great an effect on immune cell cytokine activation. These findings may explain the attenuated inflammatory response and lower cancer risk with cagA− strains in vivo.

Intracellular phosphorylation of CagA occurs at certain glutamate-proline-isoleucine-tyrosine-alanine (EPIYA) motifs. Four distinct EPIYA motifs are described (EPIYA-A, -B, -C, and -D), whose prevalence varies by geographical region. ^, The motifs further influence the CagA-induced immune response as well as the related cancer risk. The odds ratio for gastric cancer is close to 7.3 in the case of 1 EPIYA-C segment and can be up to 51 in case of 2 or more segments. ^, Also, genetic variations in further cagPAI-related genes have been demonstrated to be associated with gastric cancer.

All strains of Hp carry the vacA gene, which codes for a pore-forming, vacuolating toxin, but expression differs according to allelic variation. Approximately 50% of Hp strains express the vacA protein, which has been shown to be a very powerful inhibitor of T cell activation in vitro. Although and cagA map to different loci within the Hp genome, the vacA protein is commonly expressed in cagA+ strains. There are various forms of vacA, and the s1m1 strains are highly toxigenic. Other bacterial virulence factors, such as cagE , may play a role in the modulation of apoptosis and the host inflammatory response, thereby contributing to disease manifestations. Indeed, “virulent strains” (cagA+, cagE+, and VacA+ s1m1) appear to be more potent inducers of proinflammatory mediators than “nonvirulent strains” (cagA−, cagE−, and VacA-), possibly explaining the higher association of cagA+ strains with gastric cancer.

Dietary Risk Factors

Numerous dietary factors have been implicated as risk factors for gastric cancer. The decline in gastric cancer rates has coincided with the widespread use of refrigeration and the concomitant higher intake of fresh fruits and vegetables and lower intake of pickled and salted foods. Use of refrigeration for more than 10 to 20 years has been associated with a decreased risk of gastric cancer. Lower temperatures reduce the rate of bacterial, fungal, and other contaminants of fresh food, as well as the bacterial formation of nitrites. Additionally, high intake of highly preserved foods may be associated with increased gastric cancer risk, potentially due to higher contents of salt, nitrates, and polycyclic aromatic amines.

Much attention has been given to the effects of high nitrate intake. When nitrates are reduced to nitrite by bacteria or macrophages, they can react with other nitrogenated substances to form N -nitroso compounds that are known mitogens and carcinogens . In rats, N -nitroso compounds have been shown to cause gastric cancer. However, studies trying to link N -nitroso exposure to gastric cancer risk have been inconclusive, perhaps reflecting the fact that nitrate intake does not necessarily correlate with nitrosation levels. A Swedish cohort study found a nearly 2-fold increased risk of gastric cancer associated with high dietary nitrate intake. However, separate large cohort studies from Europe did not demonstrate an association between nitrate intake and risk of gastric cancer. ^,

Another factor implicated in the development of gastric cancer is a diet high in salt (pickled foods, soy sauce, dried and salted fish, and meat). High salt intake has been associated with higher rates of atrophic gastritis in humans and animals in the setting of Helicobacter infection and increases the mutagenicity of nitrosated food in animal models. ^, High-salt diets are associated with a roughly a 1.5- to 2-fold increased risk of gastric cancer. Cohort and case-control studies have also found an increased risk of gastric cancer associated with processed meat intake. ^, Possible mechanisms include higher bacterial loads, up-regulation of Hp cagA expression, and increased cell proliferation and p21 expression. ^{, ,} There is a clear interaction between Hp infection and dietary risk factors for gastric cancer leading to a disproportional risk increase for Hp -positive subjects with high intake of red or processed meat compared to individuals in whom only one of these risk factors is present.

Epidemiologic studies have had inconsistent findings with regard to fruit and vegetable consumption and risk of gastric cancer. Other foods or dietary factors that have been implicated as potential risk factors for gastric cancer are high intake of fried food, foods high in fat, high intake of red meat, and aflatoxins. ^, Diets with a high intake of fresh fish and antioxidants may be protective (also see later). ^, However, there are insufficient data to make definitive conclusions regarding these factors.

Cigarette Smoking

Tobacco has long been established as a carcinogen, and numerous epidemiologic studies have demonstrated an association between cigarette smoking and gastric cancer. Several large cohort studies from Europe and Asia have reported a significantly increased risk of gastric cancer among smokers. A recent meta-analysis found that, compared to never smokers, current smokers had a 1.5- to 2-fold increased risk of gastric cancer, both for the cardia and noncardia region. The authors also reported an increased association with greater amounts of smoking.

Moist snuff is a smokeless tobacco product promoted as an alternative to cigarettes that has reportedly reduced levels of carcinogenic nitrosamines. Nevertheless, results of a Swedish cohort study demonstrated a 1.4-fold increased risk of noncardia gastric cancer among regular snuff users. Snuff exposure also increases the rate of gastric carcinogenesis in Hp -infected mice.

Alcohol

Most epidemiologic studies have failed to demonstrate an association between alcohol consumption and cardia or noncardia gastric cancer. ^{, ,} However, several meta-analyses suggest a small but significant association between heavy alcohol use and gastric cancer risk (RR, 1.16-1.87 in selected subgroups). Although some of these analyses suggest that the risk is higher for junctional cancers than more distal gastric cancer, some authors state the opposite effect. Overall, the risk increase seems to be moderate and influenced by multiple factors (including tobacco consumption and physical activity). Interestingly, alcohol intake may increase the risk of gastric cancer in patients with certain polymorphisms of the alcohol dehydrogenase gene.

Obesity

Obesity is a recognized risk factor for numerous GI malignancies. Increased BMI is associated with a mild to moderate increased risk of gastric cardia cancer, but not noncardia cancer. Results of the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Cohort Study demonstrated that morbid obesity (defined as a BMI ≥35) as well as large waist circumference were associated with a 2- to 3-fold increased risk of gastric cardia cancer, but not noncardia cancer. A separate cohort study from the Netherlands also found an increased risk of cardia cancer with increasing BMI. In a recent analysis of the EPIC cohort data from 391,456 individuals with 124 incident esophageal and gastric adenocarcinomas, neither 193 cardia cancers nor 224 noncardia gastric cancers were associated with BMI. The possible association between obesity and cardia cancer risk is likely mediated by proinflammatory cytokines and adipokines produced by intra-abdominal visceral fat.

Genetic Factors

As is true for most malignancies, both genetic and environmental factors play important roles in the pathogenesis of gastric cancer. Generally, intestinal-type gastric cancer is considered largely due to environmental causes (i.e., Hp infection), whereas diffuse gastric cancer is considered a primarily genetic malignancy. In the case of intestinal-type gastric cancer, however, assigning relative values to environmental and genetic contributions is complex, given that the major environmental factor, Hp , also tends to exhibit familial clustering. Nevertheless, in the future, gastric cancer types might rather be classified by genetic alterations and grouped to molecular subgroups with distinct carcinogenic mechanisms as well as clinical behavior, than to a histologic phenotype.

Overall, 10% of cases of gastric cancer appear to exhibit familial clustering, and family history is likely an independent risk factor even after controlling for Hp status. ^, In a cohort study of relatives of patients with gastric cancer, siblings had a 2-fold increased risk of gastric cancer, adjusted for Hp infection. In a case-control study from Japan, a positive family history was associated with a significantly increased odds of gastric cancer in women (OR, 5.10), but not in men. A study from Scandinavia showed that having a twin with gastric cancer conferred a markedly higher relative risk for the disease (RR, 9.9 for monozygotic twins and 6.6 for dizygotic twins), leading the researchers to calculate that heritable factors accounted for 28% of gastric cancers, compared with 10% for shared environmental factors and 62% for nonshared environmental factors. A recent meta-analysis of 32 studies including more than 80,000 individuals reported an increased pooled relative risk of 2.35 (95% CI: 1.96 to 2.81) for subjects with a positive family history of gastric cancer; the risk was even higher (RR 2.71; 95% CI: 2.08 to 3.53) if first-degree relatives had a gastric cancer diagnosis.

Some of the familial clustering seen with intestinal-type gastric cancer may be related to genetic factors that play a role in the host immune response to Hp infection. Data from South Korea indicate that individuals with a family history of gastric cancer more frequently have both Hp infection and associated atrophic gastritis or intestinal metaplasia. In a case-control study from Scotland, relatives of patients with gastric cancer had a higher prevalence of atrophy and hypochlorhydria, but a similar prevalence of Hp infection, compared with controls. The greater prevalence of atrophy was confined to those patients with Hp infection, suggesting the possibility these individuals were perhaps exhibiting a more vigorous immune response to Hp . In a number of model systems, the development of gastric atrophy has been linked to a strong Th1 immune response. ^{, ,} Thus, it was postulated that candidate disease-susceptibility genes for gastric atrophy and cancer might be genes that participate in the innate and adaptive immune responses to Hp infection. Inflammation is modulated by an array of pro- and anti-inflammatory cytokines, and several genetic polymorphisms have been described that influence cytokine response. With the recently started next-generation sequencing approaches, we may be able to determine whether families with increased gastric cancer incidence have a genetic predisposition for a more carcinogenic immune response.

One such factor is IL-1β, an important proinflammatory cytokine and a powerful inhibitor of acid secretion. Indeed, there is an association between proinflammatory IL-1 gene cluster polymorphisms ( IL-1B encoding IL-1β, and IL-1RN encoding its naturally occurring receptor antagonist, IL-1RA) and neoplastic progression in the setting of Hp infection. Individuals with the IL-1β -31 ∗ C or -511 ∗ T and IL-1RN ∗ 2/ ∗ 2 genotypes were shown in the study to be at higher risk for developing Hp -dependent hypochlorhydria and gastric cancer. The increased risk of progression to cancer with these genotypes was in the 2- to 3-fold range compared with noninflammatory genotypes. The initial report was confirmed in other studies. Subsequently, Hwang and colleagues demonstrated that carriers of the IL-1B-511T/T genotype or the IL-1RN ∗ 2 allele had higher mucosal IL-1β levels than noncarriers and also confirmed the association between the -511T/T genotype and severe gastric inflammation and atrophy. The importance of IL-1β carcinogenesis has now been demonstrated in a transgenic study, where stomach-specific expression of human IL-1β in transgenic mice led to spontaneous gastric inflammation and cancer that correlated with early recruitment of myeloid-derived suppressor cells to the stomach. Of note, in a mouse model of Barrett esophagus and esophageal and EGJ tumors, IL-1β expression in the esophageal squamous epithelium also led to esophagitis and expansion of cardia stem cells forming gastroesophageal tumors, supporting the hypothesis that Barrett’s-associated adenocarcinoma arises from the gastric cardia resembling a gastric cancer phenotype.10

Additional associations with gastric cancer risk have been reported for genetic polymorphisms in TNF-α and IL-10. Proinflammatory genotypes of TNF-α and IL-10 were each associated with a 2-fold higher risk of noncardia gastric cancer. When combined with proinflammatory genotypes of IL-1B and IL-1RN , patients with 3 or 4 high-risk genotypes showed a 27-fold greater risk of gastric cancer. Additional studies have shown that polymorphisms of the Toll-like receptor-4 (TLR-4) gene also increases the risk of gastric cancer. Carriers of the TLR4+ 896G polymorphism had an 11-fold increased odds ratio for hypochlorhydria, and significantly more severe gastric atrophy and inflammation. Accumulated evidence suggests that the genetic predisposition to gastric cancer may be largely determined by the TLR and cytokine responses to chronic Helicobacter infection. Polymorphisms in the TLR1 seem to protect against gastric cancer development (OR 0.4; 95% CI: 0.22 to 0.72) and are furthermore related to alterations of downstream cytokine signaling. ^,

The best described form of hereditary gastric cancer is the diffuse type gastric cancer that is seen in the presence of a germline mutation in the gene CDH1 , which encodes the cell adhesion molecule E-cadherin. A large New Zealand kindred was found to have a germline mutation in the E-cadherin gene, and similar mutations have been reported in several additional kindreds, all with diffuse-type gastric cancer. The age of onset of gastric cancer in individuals with CDH1 mutations is less than 40 years but can be highly variable, and the estimated lifetime risk of gastric cancer is close to 70%. ^, Germline CDH1 mutations are also associated with familial lobular breast cancer. ^,

A small part of the familial clustering of gastric cancer can be attributed to other cancer syndromes. Patients with familial adenomatous polyposis have a prevalence of gastric adenomas ranging from 35% to 100%, and their risk of gastric cancer is close to 10-fold higher than that of the general population. Dysplastic lesions in this specific group of patients frequently arise from fundic gland polyps ( Video 54.2 ) and develop at an early age. ^, Fundic gland polyps do not otherwise tend to progress toward dysplasia. Patients with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have an approximately 11% risk of developing gastric cancer, predominantly of the intestinal type, with a mean age at diagnosis of 56 years. Patients with juvenile polyposis also have a 12% to 20% incidence of gastric cancer. ^,

Video 54.2 EGD of multiple fundic gland polyps in FAP.

In addition to the germline genetic alterations described earlier, next-generation sequencing techniques such as exome sequencing have led to the detection of new molecules and mechanisms that are involved in gastric carcinogenesis. In 8% to 10% of the gastric cancer patients, somatic mutations were identified in the ARID1A gene (also called BAF250a, SMARCF1 , or OSA1 ), an accessory subunit of the SWI-SNF chromatin remodeling complex that is involved in processes of DNA repair, differentiation, and development. Notably, cancers with EBV infection showed mutations of ARID1A in 73% of the cases. Additionally, ARID1A mutations were negatively associated with mutations in TP53 and occurred together with PIK3CA mutations. Patients with ARID1A alterations had longer recurrence-free survival, suggesting that these cancers belong to a molecular subgroup with distinct carcinogenic mechanisms as well as clinical behavior. Analysis of somatic copy number aberrations have additionally shown significantly amplified genes, including therapeutically targetable kinases such as ERBB2 , FGFR1 , FGFR2 , EGFR , and MET in gastric and gastroesophageal cancers.