There are a number of types of genetic and epigenetic changes that play a role in the predisposition to or the development of gastric carcinoma (Table 5.4). These include activation of oncogenes, growth factors and growth factor receptors, inactivation of tumor suppressor genes, DNA repair genes, and cell adhesion molecules, as well as alterations in cell cycle regulatory genes. Inherited factors interact with environmental hazards to increase gastric cancer risk in two ways: (a) germline mutations account for well-defined, but infrequent, familial cancer syndromes; and (b) polymorphisms in genes that govern cell cycling or enzymes that catalyze carcinogen detoxification may also influence gastric cancer risk. Other types of changes occur in sporadic tumors.

Inherited gastric cancer predisposition syndromes account for approximately 10% of gastric cancers. The genetic events are known for some but not all of the predispositions. The hereditary nonpolyposis colon cancer syndrome (HNPCC) is an example of the interaction of environmental hazards with germline mutations. Persons with this autosomal dominant condition are at increased risk of developing
cancer at sites other than the colon, including the stomach. HNPCC is due to a germline mutation in mismatch repair genes. The risk of gastric cancer in Korean patients who carry these mutations is 3.2-fold greater than the general population of Korea, where gastric cancer accounts for 25% of all male cancers (12). In occidental countries HNPCC-associated gastric cancer has decreased in frequency in parallel with the decline in sporadic cancer (13), as might be expected if a DNA repair defect is not challenged by genotoxic hazards. The Finnish HNPCC registry has identified 45 patients with gastric cancer in 51 HNPCC families (14), and gastric cancer was the only cancer found in 22 of these. The mean age of gastric cancer development was 6 years older than colon cancer in these HNPCC families. Like sporadic stomach cancer, but unlike most Finnish familial stomach cancers, the HNPCC cancers were intestinal in type and arose in the distal stomach.

Familial adenomatous polyposis (FAP) may involve the stomach as well as the large bowel. As in the colon, gastric cancers are preceded by the development of dysplasia. The dysplasia may be flat or in polypoid lesions including adenomas, hyperplastic polyps, and fundic gland polyps. An environmental influence is suggested by the observation that Japanese patients with FAP have more frequent gastric adenomas and cancers than westerners with FAP (15,16). This may reflect the higher Japanese exposure to gastric cancer risk factors.

Germline mutations in the E-cadherin/CDH1 gene were first recognized as a source of familial stomach cancer in a New Zealand Maori family (17), and have since been shown to have a worldwide distribution (18,19). This form of familial cancer is now termed hereditary diffuse gastric cancer (HDGC). E-cadherin is a cell adhesion protein. The loss of its function (and loss of its normal expression on the cell membrane; Fig. 5.1) due to gene mutations results in the discohesive cells that characterize sporadic diffuse gastric cancers and lobular breast cancers. It is not surprising, therefore, that familial gastric cancers associated with germline mutations in this gene are diffuse in type and that HDGC kindreds also show an increased frequency of lobular breast cancer (20). Asymptomatic patients who carry the HDGC mutation are treated with prophylactic gastrectomy since the early lesions are undetectable at the time of endoscopy (21). Multiple superficial mucosal cancers may be found at the time of gastrectomy (Fig. 5.1). The chance discovery of similar lesions in an endoscopic biopsy should alert the pathologist to a possible HDGC mutation (22). Lynch et al (13) suggest that these superficial neoplastic foci represent a widespread field effect due to promoter hypermethylation and that dysregulation of genes required for invasion and metastases are much less common.

Carriers of BRCA1/2 mutations have a substantial increase in the lifetime risk of breast and ovarian cancer. These mutations have been related to a variety of other sites as well, including the stomach. The Swedish Family Cancer Database assessed the cancer incidence in classified family members (n = 944,723) and compared their cancer experience with that of the general population of Sweden and found a twofold increase in the risk of acquiring stomach cancer before age 70 among male members of families with breast and ovarian cancer (23).

Germline p53 mutations are inherited among families diagnosed with the Li-Fraumeni syndrome. Cancers arise at diverse sites in these families (24). Interaction with environmental factors is suggested by the more common prevalence of stomach cancer in Japanese families with this syndrome than among affected American families (25). Patients with the Peutz-Jeghers syndrome are at very high relative and absolute risk for gastrointestinal and other cancers. The relative risk of stomach cancer risk with this syndrome is 213
(95% confidence interval [CI] = 96 to 368) (26). A mucoid gastric adenocarcinoma associated with germline mutation in the STK11 gene has been identified in a Japanese Peutz-Jeghers family (27).

By 1966 a large number of studies had found a consistent relationship between the diffuse type of stomach cancer and blood type A (28). It seems unlikely that blood type A has a direct role in the carcinogenic process, but it may serve as a marker for an as yet unidentified mutation, or a genetic polymorphism that increases the cancer risk by modulating the host reaction to environmental hazards. For example, the interleukin-1 (IL-1) B gene that encodes a proinflammatory cytokine is highly polymorphic (29). Gastric cancer patients are more likely to have the IL-1B-31T/IL-1RN* phenotype. Such persons mount an especially strong inflammatory response to H. pylori infection through IL-1 overexpression. The level of gastric cancer risk varies greatly depending on the association of specific genotypes of the infecting organism with different IL-B phenotypes, with an odds ratio (OR) of 87 (CI = 11 to 697) when the vacAs1 strain associates with IL-B-511*T (30). In contrast, when H. pylori strain vacAm1 associates with this phenotype, the OR is substantial but falls to 7.4 (CI = 3.2 to 17). Tumor necrosis factor-α (TNF-α), another proinflammatory protein, is increased in the gastric mucosa of persons infected with H. pylori. The TNF-α-308* allele increases TNF-α production. The risk of acquiring multifocal atrophic gastritis and gastric cancer increases in persons with the high-risk IL-1B and TNF-α genotypes (31).

Variations in glutathione-S-transferase (GST-1), an enzyme that catalyzes the conjugation of numerous carcinogens, may modify the stomach cancer risk from smoking or ingested carcinogens. The null variant of the μ form of GST-1 constitutes 40% of the Japanese population and associates with a modest increased risk of gastric carcinoma (32). A
similar association has been identified between gastric cancer and a variation in the N-acetyl transferase gene (NAT-1) (33). Aromatic and heterocyclic amine carcinogens are acetylated by NAT-1, but persons with a variant form of this enzyme lack this function. Cytochrome 450 2E1 (CYP2E1) is involved in the metabolism of environmental carcinogens. Two reports suggest that polymorphisms in this gene interact with smoking to increase the risk of gastric cancer (34). Finally, the lining of the stomach is protected from environmental insults by mucin. The MUC1 gene is polymorphic and individuals with small MUC1 genotypes have an increased risk of gastric cancer (35).

A recent Korean study has shown that polymorphisms in the DNA repair gene XRCC1 may either enhance or reduce the risk of gastric cancer in this high-risk population (36). Carriers of one haplotype (194/Trp, 280/Arg, 399Arg) are at decreased risk of gastric cancer, while those with another haplotype (194/Arg, 280/Arg, 399Arg) are at increased risk of antral cancer. The polymorphism in XRCC1 interacts with a polymorphism in adenosine diphosphate ribosyl transferase (ADPRT) in such a way that ADPRT and XRCC1 polymorphisms confer host susceptibility to gastric carcinoma possibly from reduced ADPRT–XRCC1 interactions and attenuated base excision repair, particularly in smokers (36a).

In addition to the genetic factors listed above, there are a number of somatic alterations that play a role in gastric cancer development. These include sporadic alterations in oncogenes, tumor suppressor genes, and mismatch repair genes. These genetic alterations include many that are altered in other cancers. Genetic instability, CpG island methylation, telomerase activation, and p53 mutations tend to occur early in the development of gastric cancer. Some of the more common alterations are listed in Table 5.5.

Epigenetic alterations, the most common of which is CpG island methylation of the promoter regions of cancer-related genes, are also common in gastric carcinoma. There is global DNA methylation and subsequent gene silencing in gastric cancers and its precursors and tumors showing these changes fall into the CpG island methylator (CIMP) phenotype. When the CIMP phenotype occurs, there is frequently an absence of mutation in genes that are commonly mutated in gastric cancer, such as p53 (36b). Genes that are frequently hypermethylated in the setting of Ebstein-Barr virus (EBV) include p16 and hMLH1 (36c). Promoter methylation of E-cadherin is common in the setting of H. pylori infection (36d). Sonic hedgehog, a gene important in foregut development, is also frequently hypermethylated (36e).

Environmental factors may affect gastric cancer risk directly or inversely. Several environmental hazards combine to induce distal stomach cancer; other environmental factors protect the stomach from exposure to these hazards. The risk of acquiring stomach cancer ultimately depends on which prevails.

The intestinal-type cancer so characteristic of high-risk populations is preceded by a sequence of changes that begins with inflammation and passes through atrophy and intestinal metaplasia (IM) to dysplasia and ultimately to invasive cancer (57) (Figs. 5.4 and 5.5). These changes are initiated in childhood by H. pylori infection. The dense leukocytic response that affects the superficial lamina propria and the epithelium of the mucous neck region of the gastric glands, as discussed in Chapter 4, is followed by the appearance of foci of atrophic, intestinalized mucosa at the antral–corpus junction. These changes become apparent in adolescents and young adults. The metaplastic glands and the mucosa adjacent to them show increased cell proliferation. The foci of multifocal atrophic gastritis (MAG) enlarge, fuse, and expand proximally and distally so that, by the 6th or 7th decade of life, all but a small portion of the proximal greater curvature of the corpus may be lined by intestinalized mucosa. Two forms of IM are recognized: The “complete” form faithfully reproduces small intestinal-type cells. There are subsite-dependent variations that diverge from this pattern. Some intestinalized glands lack Paneth cells, lose the ability to make some glycocalyceal enzymes, or may produce mucins similar to those of the colon, the so-called “incomplete” form of IM (58). There is a widely held view that incomplete IM carries a higher risk of carcinoma than the complete form, but the most common site for early cancer is the antral–corpus junction, where the complete form predominates. The incomplete form is best seen on the distal greater curvature of the antrum, an area that is involved in the later stages of intestinalization. Cancer risk increases with the extent of the IM; the presence of incomplete IM is synonymous with extensive IM.

The mechanisms that underlie the development of IM in MAG are complex. The development and maintenance of specific organ structures and functions in the gastrointestinal tract are regulated by CDX, a homolog of the Drosophila caudal gene, during intestinal development (59). CDX1 and CDX2 are not expressed in the normal stomach, but their mRNAs are expressed in metaplastic glands. CDX2 precedes CDX1 expression and appears to trigger IM. Transgenic mice that express CDX2 in gastric parietal cells have complete replacement of gastric mucosal glands by the full array of intestinal cells,
including goblet cells and absorptive cells (60). A mechanism for the activation of this gene has been suggested by Houghton and Wang (61). They found that, in the presence of H. pylori– generated gastritis, circulating bone marrow stem cells are recruited and engrafted into the replicating zone of the gastric mucosa. The presence of these stem cells in the gastric mucosa in patients with H. pylori gastritis may account for the extreme heterogeneity of gastric cancer and the presence of cells with a hybrid intestinal/gastric phenotype (62,63).

Serum pepsinogen levels reflect the extent of gastric mucosal intestinalization. Pepsinogen is a proenzyme activated by gastric acid to produce pepsin. It is produced in two forms: Pepsinogen group I (PGI) is only produced in the oxyntic mucosa, while pepsinogen group II (PGII) is made throughout the stomach and in Brunner glands. Replacement of oxyntic mucosa by IM results in decreasing PGI serum levels (64). A PGI level <30 ηg/mL or a PGI:PGII ratio <2 are established cut-points used in screening programs to identify patients with extensive IM and who are at especially high risk of gastric cancer (65). The predictive value of the PGI level is improved when it is combined with the H. pylori serum antibody levels, as shown in Table 5.6, adapted from a case control study (66). Similar trends are observed with the PGI:PGII ratio.

Autoimmune gastritis, as discussed in Chapter 4, is a well-recognized, but less common, gastric cancer precursor than MAG. Autoimmune gastritis and H. pylori gastritis may coexist in most patients with pernicious anemia and the titers of both antibodies inversely relate to disease duration (67). It may be distinguished from late-stage MAG by the absence of antral inflammation and atrophy. The cancers associated with this form of gastritis arise in the antrum or the atrophic corpus, with a relative risk ranging from 2.2 to 5.6 (68). The increased risk stems from several factors: (a) Loss of gastric acidity favors the growth of bacteria that may generate endogenous nitroso compounds from dietary amines. (b) Gastrin production is greatly increased in response to prolonged achlorhydria. The trophic effects of hypergastrinemia result in accelerated cell turnover in a replicating compartment already expanded due to the loss of parietal and chief cells. (c) These replicating cells are exposed to reactive oxygen species from inflammatory cells.

A stage is reached in the early phases of the expansion of MAG when the proximal antral intestinalized mucosa is
exposed to the acid produced by the still intact oxyntic mucosa. The intestinalized mucosa lacks the protective mucous barrier of the normal antrum, so that it is vulnerable to peptic ulceration. Patients with gastric ulcer are at greatly increased risk of gastric cancer. This is not surprising since gastric ulcer and gastric cancer share the same risk factors: H. pylori gastritis, a diet rich in salt, smoking (48), and a declining frequency in Western countries (69). As may be expected among patients who have retained the ability to make acid, the mean age of gastric ulcer patients is 10 years younger than the mean age of patients with cancer. Re-epithelialization of the ulcer associates with expansion of the replication zone of the glands bordering the ulcer, exposing a larger number of vulnerable proliferating cells to genotoxic hazards. In contrast, the regenerating epithelial cells that migrate over the ulcer base are arrested in the postmitotic phase of the cell cycle, accounting for the observation that the gastric mucosa bordering the ulcer, rather than the ulcer base, is a common site of early cancer.

The term ulcer cancer defines a gastric carcinoma that arises in a pre-existing peptic ulcer (Figs. 5.6 and 5.7). Tumors arising in this setting account for <1% of all gastric
carcinomas. In order to be accepted as an ulcer cancer, the case must show definite evidence of pre-existing chronic peptic ulcer and evidence of coexisting malignancy. About 5% of endoscopically benign ulcers eventually prove to be malignant, but some lesions may require more than one biopsy to detect the underlying malignancy (70). Underestimation of the depth of invasion may occur when the tumor develops from the epithelium of a healed ulcer in which the submucosa and muscularis propria are no longer recognizable because of scarring.

Hyperplastic polyps used to constitute from 75% to 90% of all gastric polyps (71). They arise from the foveolar hyperplasia that frequently accompanies atrophic gastritis, whether of the multifocal or autoimmune type. They may also appear on the gastric side of gastroenterostomy stomas. Patients with hyperplastic polyps are at increased risk of gastric cancer, but the cancers very rarely arise in them. Rather, they are byproducts of the chronic gastritis that is the underlying cause of cancer induction. In the unusual event that a cancer does arise in a hyperplastic polyp, it is preceded by the development of dysplasia (Fig. 5.8).

Dysplasia is the first microscopically detectable anatomic change in the neoplastic process. The dysplastic changes may represent cytologic alterations or disorganized architecture. Gastric dysplasia shows two major growth patterns: A flat, grossly inconspicuous dysplasia or polypoid lesions recognizable as adenomas. The dysplastic cells may be gastric or intestinal in type, or they may be hybrid forms from each lineage.