Gastric Cancer
A number sign (#) is used with this entry because somatic mutations in various genes have been identified in gastric cancer tumor tissue. These genes include APC (611731), IRF1 (147575), KLF6 (602053), MUTYH (604933), KRAS (190070), CASP10 (601762), PIK3CA (171834), ERBB2 (164870), and FGFR2 (176943).
DescriptionIn a review article on the genetic predisposition to gastric cancer, Bevan and Houlston (1999) concluded that several genes may be associated with an increased risk of gastric cancer.
Gastric cancer is a manifestation of a number of inherited cancer predisposition syndromes, including hereditary nonpolyposis colon cancer (HNPCC1; see 120435), familial adenomatous polyposis (FAP; 175100), Peutz-Jeghers syndrome (PJS; 175200), Cowden disease (CD; 158350), and the Li-Fraumeni syndrome (151623). See also hereditary diffuse gastric cancer (HDGC; 137215).
Canedo et al. (2007) provided a review of genetic susceptibility to gastric cancer in patients infected with Helicobacter pylori (see 600263).
Clinical FeaturesScott et al. (1990) described a family in which 2 of 4 sibs under the age of 40 years presented with gastric cancer. A third sib had antrectomy for gastric dysplasia, and a fourth, aged 36, had extensive chronic atrophic gastritis and intestinal metaplasia. Of 8 children of these 4 individuals, 5 had Helicobacter pylori-positive, chronic atrophic gastritis, and in 3 of the 5, intestinal metaplasia developed in the gastric antrum but not in the body. Scott et al. (1990) postulated that the family was segregating a genetic predisposition to the metaplasia/dysplasia/carcinoma sequence described by Correa (1988). Helicobacter pylori, previously designated Campylobacter pylori, may have acted as a promoter in the progression from normal to metaplastic epithelium, possibly by inducing a hyperproliferative state in the inflamed gastric mucosa. Scott et al. (1990) noted that the gastric tumors in this family were consistent with the intestinal type, rather than the diffuse type.
Kakiuchi et al. (1999) studied the clinical features of the probands of 16 Japanese families with gastric cancer, defined as the existence of 3 or more family members with gastric cancer in at least 2 successive generations. Seven patients (44%) developed cancer in the cardiac region of the stomach, which was significantly higher than for gastric cancer in the general population in Japan (15.4%). The cancers were more often of the undifferentiated type (69%), and showed an increased frequency of disseminated peritoneal (40%) and liver metastases (20%) compared to gastric cancer in the general Japanese population. These unique characteristics suggested a genetic background in their etiology.
InheritanceZanghieri et al. (1990) and La Vecchia et al. (1992) found that about 10% of gastric cancer cases show familial clustering. Epidemiologic studies have shown that the risk of gastric cancer in first-degree relatives is increased 2- to 3-fold (Goldgar et al., 1994).
In a review, Gonzalez et al. (2002) noted that human gastric carcinogenesis best fits a multifactorial model, according to which different dietary and nondietary factors, including genetic susceptibility, are involved at different stages in the cancer process.
Population GeneticsDespite a declining incidence (Howson et al., 1986), gastric cancer is a major cause of cancer death worldwide. Gonzalez et al. (2002) observed that gastric cancer constitutes the second most frequent cancer in the world and the fourth in Europe.
In a nationwide epidemiologic study in Sweden, Hemminki and Jiang (2002) found that the population-attributable proportion of familial gastric carcinoma was much lower than that cited in the literature. Patterns of multiple carcinomas suggested that immunologic factors modulate susceptibility to gastric carcinoma. The authors concluded that environmental factors, perhaps H. pylori infections, were the main reason for familial clustering of gastric carcinoma.
PathogenesisLauren (1965) defined 2 main histologic types of gastric carcinomas, a 'diffuse' type and a so-called 'intestinal' type. Diffuse tumors, as observed in hereditary diffuse gastric carcinoma (HDGC; 137215), are poorly differentiated infiltrating lesions resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. This classification system was updated in 1995 to include 4 main types of gastric cancer: isolated cell and mixed types (representing the diffuse component); and glandular/intestinal and solid (representing the non-diffuse component).
The association of gastric cancer with blood group A and pernicious anemia has been known for a long time. Thomsen et al. (1981) found that the HLA-DR5 genotype was associated with a 6-fold increase in risk of pernicious anemia (261000), suggesting that events leading to gastric cancer have a genetic component.
Palli et al. (2001) evaluated the relation between dietary habits (particularly consumption of red meat) and MSI status using 126 gastric cancer cases and 561 population controls identified in a case-control study carried out in a high-incidence area around Florence, Italy. An MSI-positive phenotype was detected in 43 of 126 cases (34.1%). A risk of MSI-positive tumors was positively associated with consumption of red meat and meat sauce and negatively associated with consumption of white meat. Risk was especially high among subjects reporting both a positive family history for gastric cancer and a high consumption of red meat. The risk of MSI-negative tumors was strongly reduced by the frequent consumption of fresh fruits and vegetables.
Gonzalez et al. (2002) stated that Helicobacter pylori infection is an established risk factor of gastric cancer, but gastric cancer occurs in only a very small proportion of people infected with the organism. Infection by H. pylori may result in gastric cancer through induced hyperproliferation of gastric cells, interference with antioxidant functions, and increased amounts of reactive oxygen species and nitric oxide, which may be responsible for oxidative DNA damage.
Berman et al. (2003) demonstrated that a wide range of digestive tract tumors, including most of those originating in the esophagus, stomach, biliary tract, and pancreas, but not in the colon, display increased hedgehog pathway activity, which is suppressible by cyclopamine, a hedgehog pathway antagonist. Cyclopamine also suppresses cell growth in vitro and causes durable regression of xenograft tumors in vivo. Unlike tumors in Gorlin syndrome (109400), pathway activity and cell growth in these digestive tract tumors are driven by endogenous expression of hedgehog ligands, as indicated by the presence of Sonic hedgehog (600725) and Indian hedgehog (600726) transcripts, by the pathway- and growth-inhibitory activity of a hedgehog-neutralizing antibody, and by the dramatic growth-stimulatory activity of exogenously added hedgehog ligand. Berman et al. (2003) concluded that their results identified a group of common lethal malignancies in which hedgehog pathway activity, essential for tumor growth, is activated not by mutation but by ligand expression.
Houghton et al. (2004) showed that although acute injury, acute inflammation, or transient parietal cell loss within the stomach do not lead to bone marrow-derived stem cell recruitment, chronic infection of C57BL/6 mice with Helicobacter, a known carcinogen, induced repopulation of the stomach with such stem cells. Subsequently, these cells progressed through metaplasia and dysplasia to intraepithelial cancer. Houghton et al. (2004) suggested that epithelial cancers can originate from marrow-derived sources and thus have broad implications for the multistep model of cancer progression.
Chien et al. (2006) studied HTRA1 (PRSS11; 602194) expression in tumors from 60 patients with epithelial ovarian cancer (167000) and 51 with gastric cancer and found that those with tumors expressing higher levels of HTRA1 showed a significantly higher response rate to chemotherapy than those with lower levels of HTRA1 expression. Chien et al. (2006) suggested that loss of HTRA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance.
MappingLoss of heterozygosity at chromosomes 1p, 5q, 7q, 11p, 13q, 17p, and 18p has been observed in a high proportion of gastric cancer tissues (Motomura et al., 1988; Kim et al., 1995).
Aoki et al. (2005) performed a genomewide screen for gastric cancer susceptibility genes in 170 affected sib pairs from 142 Japanese families. Nonparametric linkage analysis revealed the strongest signal to be on chromosome 2q33-q35, with multipoint and 2-point lod scores of 1.74 and 1.98, respectively. Analysis of a subgroup with proximal gastric cancer increased the signal of linkage to 2q33-q35 to multipoint and 2-point lod scores of 3.61 and 2.93, respectively (p = 0.002 by simulation studies). Aoki et al. (2005) suggested that there is a gastric cancer susceptibility locus on chromosome 2q33-q35.
Molecular GeneticsGermline Mutations in Cancer Predisposition Syndromes
Carriers of germline mutations in mismatch repair genes (see, e.g., MLH1, 120436) have a 4-fold increased risk of gastric cancer in addition to the high risk of colorectal cancer (Lynch and Smyrk, 1996; Watson and Lynch, 1993). Mutations in mismatch repair genes result in microsatellite instability (MSI). Although MSI is seen in 20 to 30% of cases of gastric cancer (Renault et al., 1996), germline or somatic mutations in these MMR genes are rarely seen in sporadic or familial non-HNPCC gastric cancer (Keller et al., 1996). Ottini et al. (1997) showed that microsatellite instability was significantly associated with distal (antral) tumors of the stomach and a positive family history of gastric cancer.
Ottini et al. (1997) showed that microsatellite instability was significantly associated with distal (antral) tumors of the stomach and a positive family history of gastric cancer.
Gonzalez et al. (2002) reviewed published evidence on the contribution of genetic susceptibility to gastric cancer risk in humans. Most of the studies assessed the effect of genes involved in detoxifying pathways and inflammatory responses. The most consistent results were the increased gastric cancer risk associated with interleukin 1-beta (IL1B; 147720) and N-acetyltransferase-1 (NAT1; 108345) variants, which may account for up to 48% of attributable risk of gastric cancer. Polymorphisms at the HLA-DQ (146880), tumor necrosis factor (TNF; (191160), and CYP2E 124040) genes may confer some protective effect against gastric cancer.
El-Omar et al. (2000) found that individuals carrying the IL1B -31 T polymorphism (147720.0001) were at a higher risk of hypochlorhydria and of gastric cancer after H. pylori infection. El-Omar et al. (2000) found that IL1RN*2 (147679.0001) homozygotes were at increased risk of hypochlorhydria and gastric cancer. Risk for these disorders among IL1RN*2 heterozygotes was not significantly increased.
Huntsman et al. (2001) noted that hereditary gastric cancer predisposition syndromes and CDH1 (192090) germline mutations contribute very little to the overall load of new gastric cancer cases.
In a 2-stage genomewide association study of Japanese patients with gastric cancer and controls, the Study Group of Millennium Genome Project for Cancer (2008) identified a significant association between 2 SNPs in the PSCA gene (602470), rs2976392 and rs2294008, and diffuse-type gastric cancer (allele-specific odds ratio = 1.62 and 1.58, respectively; p = 1.11 x 10(-9) and 6.3 x 10(-9), respectively). The SNPs were in strong linkage disequilibrium with each other; the authors noted that in functional studies, the risk allele 'T' of rs2294008 reduced transcriptional activity of an upstream fragment of the gene, suggesting that rs2294008 was the functional SNP. The same risk allele of rs2294008 was also significantly associated with diffuse-type gastric cancer in Korean patients and controls (allele-specific OR = 1.90; p = 8.01 x 10(-11)). The authors concluded that polymorphism of the PSCA gene influences susceptibility to diffuse-type gastric cancer.
In a Korean population, Kwon et al. (2010) presented evidence suggesting that variation in polymorphic microsatellite repeats in the MUC6 gene (158374) may influence susceptibility to gastric cancer by regulating expression of the MUC6 gene.
Somatic Mutations
Inactivation of the APC gene (611731) is seen in about 20% of early sporadic gastric cancer (Hsieh and Huang, 1995). Horii et al. (1992) detected somatic mutations in the APC gene (611731.0010; 611731.0011) in tumor tissue of 3 of 44 gastric cancers.
In a human gastric cancer cell line, Nozawa et al. (1998) found a somatic point mutation in the IRF1 gene (147575.0001).
In a set of 80 gastric cancer tissues, Cho et al. (2005) identified 4 somatic missense mutations in the KLF6 gene (see, e.g., 602053.0006); the mutations were absent from corresponding normal tissue. In addition, 16 (43.2%) of 37 informative cases showed allelic loss at the KLF6 locus. All of the cases with mutation and 13 of the 16 with allelic loss were of advanced intestinal-type gastric cancer with lymph node metastasis.
In gastric cancer tissue from 2 unrelated patients who were carriers of H. pylori, Kim et al. (2004) identified heterozygous somatic mutations in the MUTYH gene (604933.0006 and 604933.0007, respectively) and loss of the remaining allele.
Park et al. (2002) identified somatic mutations in the CASP10 gene (see, e.g., 601762.0004 and 601762.0006) in 3 of 99 gastric cancers.