Association Of MnSOD T5482C Single Nucleotide Polymorphisms With Susceptibility To Gastric Cancer

Background: Gastric cancer is one of the most common malignanciesworldwide. The highest gastric cancer incidence rate in the world takes place inEast Asia. The development of gastric cancer has been shown to be amulti-factorial process, which is associated with a variety of risk factors,including genetic predisposition, advanced age, alcohol consumption, smoking,diet and Helicobacter pylori (H. pylori) infection. At the molecular level, theinitiation of cancers is believed to be a consequence of accumulated geneticdamages leading to genetic alterations. DNA damage caused by oxidative stressis the most frequent type encountered in aerobic cells. Reactive oxygen species(ROS) are generated during normal aerobic metabolism. The effects of ROScan be both beneficial and harmful. At low levels, ROS can induce a mitogeniceffect and participate intracellular signaling pathways. The high level of ROSleading to oxidative stress could induce DNA damage and has been shown tobe involved in the etiology of several diseases including cancer. ROS can begenerated by cigarette smoking, chronic hypoxia, radiation from theenvironment and intracellular cytokines (TNF-α, IFN, IL-1, and IL-6). Forgastric cancer, chronic inflammatory stress and radiation from the environmentare two particularly important ROS-generating factors. These harmful effects ofROS are protected by both enzymatic and non-enzymatic antioxidants. MnSuperoxide dismutase (MnSOD) is important in avoiding oxidative stress byeliminating ROS which can cause the oxidative stress. Single nucleotidepolymorphism is known as the third generation of genetic markers which hascharacteristics of knowable, detected and hereditary. It is of great significanceto study individual susceptibility to different diseases or to identify individual for a particular drug response. So far, it is widely concerned of the relationshipbetween single nucleotide polymorphism susceptibility and disease. TheT5482C genetic variant results in a C to T substitution within exon2ofMnSOD gene leading to an amino acid switch from alanine to valine. Thispolymorphic aberration has been associated with an increased risk of cancers.Method： To determine whether single nucleotide polymorphisms atT5482C within MnSOD are associated with susceptibility to gastric cancer, weinvestigated the genotype and allele frequencies of the genes from294gastriccancer patients and300healthy individuals in Catholic University of Korea,Seoul Mary Hospital. A PCR-SSCP assay was used to identify the MnSODT5482C genotype.Result: Statistically significant differences in the genotype and allelefrequencies of MnSOD T5482C were found between the healthy controls andgastric cancer patients (P=0.0001and P <0.0001, respectively). In theunconditional logistic regression model, the carriers with T/C genotype had2.115fold higher risk to gastric cancer than that with T/T genotype (95%CI=1.308-3.420), and the C/C genotype is3.958fold higher risk than T/T genotype(95%CI=1.211-12.933). In the unconditional logistic regression model, furthertrend test results showed that the carriers with one more C allele will increased2.066fold higher risk to gastric caner(95%CI=1.394-3.063). When the datawere stratified according to gastric cancer histological subtypes, there arestatistically significant differences between diffused and intestinal gastriccancer and healthy control. The carriers with C allele increased the risk ofdiffused and intestinal gastric cancers, respectively.Conclusion: Our findings suggest that polymorphism of the MnSODT5482C was closely associated with susceptibility to gastric cancer in theKorean population. The C allele of the MnSOD T5482C increased the risk ofgastric cancer. The C variant may be closely related with the lower activity of MnSOD, which reduced the ability to eliminate ROS. The polymorphism of theMnSOD T5482C was closely associated with susceptibility to diffused andintestinal gastric cancers, respectively.