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 angiogenesis2.

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 p27 3,4 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

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