Page 20 - Helicobacter pylori and Gastric Cancer: From Tumor microenvironment to Immunotherapy

Chapter 1
General introduction
(HDGC). The identification of a germline mutation inactivating the gene encoding for E-cadherin (CDH1) in a Maori family from New Zealand was the start point to understand HDGC pathogenesis. In HDGC families, abnormal E-cadherin gene carriage is found associated to an 80% risk (Lifetime) for Gastric cancer development, leading to recommendations for genetic testing, screening, and even total gastrectomy as a prophylactic strategy in CDH1 mutation carriers(43). Other inherited predisposition syndromes include Lynch syndrome, which shows an intestinal histology in 90% of the cases, and carries a lifetime risk of around 10% for gastric cancer (of note, this risk is much higher for colorectal or endometrial cancer); ovarian and breast cancer hereditary syndrome because of germline mutations of BRCA1 and BRCA2; p53 mutations that preceeded Li-Fraumeni syndrome; and the much rarer familial adenomatous and juvenile polyposis syndromes which are associated with the hererozygotic carriage of APC gene germline mutations, BMPR1A and SMAD4 genes, and STK11 gene, respectively(44). The relationship with the BMP pathway and gastric cancer is intriguing. BMP pathway activity and Hedgehog pathway are closely linked, and in contrast to the BMP pathway, exaggerated Hedgehog pathway activity is subject to treatment by FDA and EMA- approved pharmacological inhibitors. This is one of the factors (see also below) that drove me in the course of this research to explore the potential of the Hedgehog pathway in gastric carcinogenesis.
Other Miscellaneous Factors
Pernicious anemia can result from an autoimmune disorder characterized by atrophic damage restricted to the gastric body mucosa (gastric atrophy type A). This condition confers significant risk for gastric cancer development, with a similar incidence rate as seen in gastric atrophy caused by H. pylori (gastric atrophy type B)(45). The associated risk appears H. pylori infection independent, although the potential interaction between infection and pernicious anemia has not yet been thoroughly studied. Prior gastric surgery for benign disorders (mainly gastric ulcer) was an established risk factor for adenocarcinoma development before the discovery of H. pylori. It is not clear if a prior gastric surgery is itself associated gastric cancer risk factor in the remnant stomach (e.g., acting synergically with H. pylori through mechanical adverse effects of the surgery, i.e., bile reflux) or if it is merely a surrogate for long-term infection with H. pylori with the more aggressive CagA positive strains(46, 47). Ionizing radiation has been shown to provoke risk for cancer development, including gastric carcinoma(40). The best evidence comes from the an
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