In 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 ... In 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).
Scott 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 ... Scott 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.
- Germline 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 ... - Germline 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), dbSNP rs2976392 and dbSNP 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 dbSNP rs2294008 reduced transcriptional activity of an upstream fragment of the gene, suggesting that dbSNP rs2294008 was the functional SNP. The same risk allele of dbSNP 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.
Despite 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 ... Despite 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.