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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 to be 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,102 and family history is likely an independent risk factor even after controlling for Hp status.103,104 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.105 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.106 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.107

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.108 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.109 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.36,40,110 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 development of Hp-dependent hypochlorhydria and gastric cancer.111 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.112-116 Subsequently, Hwang and colleagues117 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 (MDSCs) to the stomach.118 Of note, in a mouse model of Barrett’s 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, suggesting that Barrett’s-associated adenocarcinoma comes from the gastric cardia.9

Additional associations with gastric cancer risk have been reported for genetic polymorphisms in TNF-α and IL-10. Pro- inflammatory genotypes of TNF-α and IL-10 were each associ- ated 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.119 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.120 Accumulated evidence suggests that the genetic predisposition to gastric cancer may be largely determined by the TLR and cytokine responses to chronic Helicobacter infection.

The best described form of hereditary gastric cancer is the diffuse 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.121-124 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%.125,126 Germline CDH1 mutations are also associated with familial lobular breast cancer.127,128

A small part of the familial clustering of gastric cancer can be attributed to other cancer syndromes. Patients with familial adenomatous polyposis (FAP) 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.129 These cancers frequently arise from fundic gland polyps and develop at an early age.130,131 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.132 Patients with juvenile polyposis also have a 12% to 20% incidence of gastric cancer.133,134

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, a somatic mutation was recently identified in 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.135-138 Notably, cancers with Epstein-Barr virus 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.135-138 Analysis of somatic copy number aberrations (SCNAs) have additionally shown significantly amplified genes, including therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET in gastric and gastroesophageal cancers.17