Host genetic factors in gastric cancer

Abstract

Helicobacter pylori infection is associated with divergent clinical outcomes that include peptic ulcer disease and gastric cancer. The key determinants of these outcomes are the severity and distribution of the H. pylori-induced gastritis. Host genetic factors are emerging as key determinants of disease risk for many cancers. In the case of H. pylori-induced gastric cancer, the most relevant candidate genes are those that impact on the inflammatory response to the infection (e.g. interleukin-1(beta) (IL-1(beta)), tumour necrosis factor-(alpha) (TNF(alpha)), IL-8 and IL-10, IFNG receptors and several others). Genetic polymorphisms of the innate immune response genes such as TLR4 and MBL have also been shown to increase risk for gastric cancer and its precursors. Genome Wide Association Studies (GWAS) have recently identified novel risk markers including ones in the Prostate Stem Cell Antigen (PSCA rs2294008 C>T). Remarkably, The C allele of this polymorphism was associated with decreased risk of gastric cancer but an increased risk of duodenal ulcer. This finding is entirely consistent with the observed epidemiology of duodenal ulcer disease, which seems to protect against gastric cancer. This polymorphism also appears to be functional. The T allele of rs2294008 encodes a translation initiation codon upstream of the reported site and changes protein localization from the cytoplasm to the cell surface. Another GWAS study identifi ed two new loci 5p13.1 (rs13361707 in the region including PTGER4 and PRKAA1) and 3q13.31 (rs9841504 in ZBTB20). These studies were carried out in Asian populations and the findings require validation in other ethnic groups. The exciting findings from GWAS studies highlight the prospect of developing a panel of genetic risk markers that could predict likelihood of developing gastric cancer. Such a panel would be a major advance in the fight against gastric cancer but it must undergo rigorous validation in a well designed prospective manner.