| Gastric cancer is a common cancer and it still remains a significant cancer burden currently and is one of the key issues in cancer prevention and control strategy in China.Gastric tumors are classified anatomically as proximal (also known as cardia) and distal (also known as noncardia).The latter are commonly associated with infection of Helicobacter pylori, but the former are not. Gastric adenocarcinomas are defined as well differentiated (also known as intestinal-type) and undifferentiated (also known diffuse-type).intestinal-type tumors are found predominantly in geographic areas with a high incidence of gastric cancer (for instance, in China), whereas diffuse-type tumors are found more uniformly throughout the world. The exact mechanisms of the gastric cancer are still unknown. It was well-documented that some kind of cancers may result from chronically inflamed tissues, particularly in the gastrointestinal tract. In contrast to the largely vascular changes of acute inflammation, chronic inflammation is characterized by infiltration of damaged tissue by mononuclear cells, such as macrophages, lymphocytes, and plasma cells, with concurrent tissue destruction and repair. Therefore, chronic inflammation is a common underlying process in the development of many gastrointestinal malignancies, including gastric cancer and become one of the hot researches on cancer. The inflammation is mediated by an array of pro- and anti-inflammatory cytokines. Among the variance cytokine, the interleukin2 (IL2) is a typical Th1 cytokine, the interleukin4 (IL4) is an inducible Th2 cytokine and interleukin12 is an inducible Th1 cytokine which is critical in the H.pylori-related gastritis and even the gastric cancer. These cytokines are critical mediators of the Th1/Th2 balance and apoptosis and involved in the process of inflammation-mediated carcinogenesis in human organs, including the gastrointestinal tract. Thus, we make the hypothesis that the genetic variation of IL2, IL4 and IL12 may be associated with the occurrence and development of gastric cancer.[Objective] Based on the important role of IL2,IL4 and IL12 in the gastric carcinogenesis, we hypothesized that the promoter variants of IL2 (rs2069762) and IL4 (rs2070874)and 3'UTR of IL12B (rs3212227) were associated with gastric cancer susceptibility.[Methods] We genotyped the two promoter polymorphisms in IL2 G-330T (rs2069762) and IL4 T-168C (rs2070874) and one 3'UTR polymorphism of IL12B gene A1188C (rs3212227) in a case-control study of 1045 patients with incidence gastric cancer and 1100 cancer-free controls, which was matched with cases on sex, age(±5 yr), and region, in a high-risk Han Chinese population.[Results] The logistic regression revealed that TT homozygote of IL2 was associated with significantly reduced risk of gastric cardia cancer (adjusted OR=0.66, 95%CI=0.44-0.99), compared with GG genotype. Compared with the TT genotype, the TC heterozygote of IL4 was associated with decreased risk of the whole gastric cancer (adjusted OR=0.81, 95%CI=0.67-0.98), besides, TC heterozygote of IL4 could also reduce the risk of gastric cardia cancer (adjusted OR=0.70, 95%CI=0.54-0.92), among the non-cardia cases, the association did not reach the statistic significance (adjusted OR=0.96, 95%CI=0.73-1.26). We did not find significant association between IL12B variant genotypes and gastric cancer risk (adjusted OR=0.89, 95%CI=0.73-1.09 for AC genotype and adjusted OR=0.92, 95%CI=0.71-1.20 for CC genotype, respectively). When we combined the two SNPs of IL2 and IL4, we found that individuals carrying -330GT/TT and -168TC/CC could marginally decrease the risk of gastric cardia cancer (P=0.05).Subjects with GT/TT genotype of IL2 were associated with a reduced gastric cardia cancer risk among younger persons (less than 60 years), men, smokers and drinkers (adjusted OR=0.52, 95%CI=0.29-0.93 for the younger, adjusted OR=0.52, 95%CI=0.33-0.81 for men, adjusted OR=0.53, 95%CI=0.31-0.92 for smokers, and adjusted OR=0.40, 95%CI=0.19-0.83). For IL4, subjects with TC/CC genotype have a reduced gastric cancer risk in men (adjusted OR=0.77, 95%CI=0.61-0.97). However, the TC/CC genotype could decrease the gastric cardia risk among the younger, men and smokers. We only found the AC/CC genotype of IL12B could reduce the gastric cancer among drinkers.[Conclusion] Our findings suggested that promoter polymorphisms of IL2 and IL4 may modulate the risk of gastric cancer and the IL12B gene (A1188C) polymorphism may not contribute to gastric cancer susceptibility in China. Larger studies and functional studies are needed to confirm our findings. |
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