Cancer Research UK : Stomach Cancer molecular biology and genetics

Stomach Cancer molecular biology and genetics

This page contains information on the molecular biology and genetics relating to stomach cancer

Chronic infection with Helicobacter pylori (H.pylori) leads to chronic gastric inflammation, which in turn increases the risk of developing stomach cancer. However this risk is dependent upon variable factors in both the individual and the bacterial strain(s) with which they are infected.1,2

For example, variation in the strength of immune and inflammatory responses to H. pylori infection is important. Genetic variations (polymorphisms), which enhance the inflammatory response, such as those in genes producing inflammatory cytokines ,(e.g. IL-1B, IL1RN, TNF-A and IL-10), have been associated with increased gastric cancer risk.1,2

H. pylori infection induces inflammation through activation of NF-kB and its pro-inflammatory transcriptional targets in the gastric cells.2 Pro-inflammatory Cox-2 is also induced, and in turn facilitates tumour growth via inhibition of apoptosis, increased cellular proliferation and stimulation of angiogenesis 2.

Differences in the expression of various bacterial genes can also affect the risk of stomach cancer.

Strains which express the genes CagA, BabA and SabA, increase the risk of developing stomach cancer, as do certain genetic variants of the VacA gene.1,2

As well as the induction of inflammation, this increased risk is also due to direct effects on the proliferation and apoptosis of gastric epithelium cells.1,2 For example, the presence of the bacterium also induces cell cycle arrest, both through the reduced expression of the cell cycle regulatory protein p273,4 and through direct damage to host cell DNA,5,6 for example by the production of reactive oxygen and nitrogen species.2

The presence of the bacterium is also thought to interfere with gastric antioxidant defence mechanisms.7

The host response to H. pylori infection has also been shown to promote cellular proliferation by inducing the production of gastrin,8 although the exact role of this hormone in the development of gastric cancer remains unknown.9

As well as variations in inflammatory response genes, several other genetic changes have been identified in gastric cancers.

These include the activation or amplification of the oncogenes c-met, K-sam and c-erbB2 and inactivation of the tumour suppressor genes p53, APC, bcl-2 and RUNX3. In addition, genes of the E-cadherin family, involved in cell adhesion, are often lost.2

Approximately 10% of gastric cancers cluster in families. Hereditary diffuse gastric cancer is a rare form of the disease with autosomal dominant inheritance. The E-cadherin gene, CDH1, is mutated in around 25% of inherited cases.10

References for stomach cancer molecular biology and genetics

Peek, R.M., Jr. and J.E. Crabtree, Helicobacter infection and gastric neoplasia. J Pathol, 2006. 208(2): p. 233-48
Smith, M.G., et al., Cellular and molecular aspects of gastric cancer. World J Gastroenterol, 2006. 12(19): p. 2979-90
Shirin, H., et al., Helicobacter pylori inhibits the G1 to S transition in AGS gastric epithelial cells. Cancer Res, 1999. 59(10): p. 2277-81
Ahmed, A., et al., Helicobacter pylori inhibits gastric cell cycle progression. Microbes Infect, 2000. 2(10): p. 1159-69
Baik, S.C., et al., Increased oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. Cancer Res, 1996. 56(6): p. 1279-82
Smoot, D.T., et al., Influence of Helicobacter pylori on reactive oxygen-induced gastric epithelial cell injury. Carcinogenesis, 2000. 21(11): p. 2091-5
Sobala, G.M., et al., Effect of eradication of Helicobacter pylori on gastric juice ascorbic acid concentrations. Gut, 1993. 34(8): p. 1038-41
Levi, S., et al., Campylobacter pylori and duodenal ulcers: the gastrin link. Lancet, 1989. 1(8648): p. 1167-8
Watson, S.A., et al., Gastrin - active participant or bystander in gastric carcinogenesis? Nat Rev Cancer, 2006. 6(12): p. 936-46
Oliveira, C., et al., Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred. Hum Mutat, 2002. 19(5): p. 510-7

Stomach Cancer molecular biology and genetics

References for stomach cancer molecular biology and genetics

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