A Molecular Epidemiological Study On The Relationship Between The Genetic Polymorphism Of GSTP1 In Population In The Northeast China And Susceptibility To Gastric Cancer

PrefaceIn the world, gastric cancer is still one of the most frequent types of cancer. Gastric cancer is a leading cause of malignancy - related death in China, especially in high incidence areas. The estimate for 2004 points, in China, to the second place in incidence and mortality with about 300. 87/100,000 and 29. 31/ 100,000. Specially, in the Northeast China, mortality of male was 49. 55/100, 000 and that of female was 22. 23/100,000. So far, through the investigations about pathogenesis of gastric cancer, increasing evidence suggests that interaction between various inherited cancer susceptibility genes, also known as risk — modifier genes, particularly genes whose allelic polymorphism are responsible from impaired ability to metabolize environmental carcinogens and/or repair DNA damage from oxidative stress, coule affect an individual's risk of developing cancer.Since the first description that the polymorphisms of the RAS gene can be used to value the risk of oncogenesis by Krontiris in 1985, more studies have begun to demonstrate associations between the polymorphisms and gastric cancer susceptibility that included the metabolic enzymes genes, oncogenes, anti - on-cogenes and immuno - modifier genes. It has been suggested that genetic susceptibility genes, specially metabolising enzymes genes, may confer a risk for the development of gastric cancer. Cytochrome P450, as phase I metabolic enzymes , can be induced by ethanol and catalyses the oxidation of many substrates , including several potential carcinogens and drugs that are transformed totheir ultimate reactiveforms. Glutathione S - transferases ( GSTS) consist of a su-perfamily of dimeric phase II metabolic enzymes that are separated into the four classes: GSTA( alpha) .GSTM(mu),GSTT(theta) and GSTP( pi). The polymorphisms in GSTM1 and GSTT1 were investigated in cancers for a long time, however, only recently some studies were conducted to investigate the association of various cancers with GSTPl variants. In 1989, Board reported the isolation of full - length cDNAs of GSTPl gene. The GSTPl gene has been mapped to a relatively small region of chromosome Ilql3. Polymorphisms of GSTPl have been reported for example, isoleucine(He) 105 valine(Val) in exon5, alanine (Ala) 114 valine( Val) in exon 6. GSTPl is subject to polymorphic variations;the single — nudeotide substitution A/G results in an amino acide change at co-don 105 (He—?Val) that is associated with lower substrate - specific catalytic activity and lower thermal stability for the encoded protein ( GSTir). A 2^3 fold reduction in thermal stability has been shown in association with the GSTPl 105Val variant compared with the GSTPl 105Ile variant. But the polymorphic site at nucleotide 114 ( exon 6) was detected and found to no modify the enzyme's activity and affinity for electrophilic substrates. That is to say, the two GSTPl proteins differ in specific activity, affinity for electrophilic substrates and heat stability. The GSTPl — valine variant has lower activity toward 1 - chloro — 2,4- dinitrobenzene but greater activity toward bromosulfophthalein and ethacrynic acid. In addition, the GSTPl -isoleucine, which has higher activity for most substrates than GSTPl -Valine, is less thermostable.To date, the nucleotide sequences of the complete human GSTPl cDNA and the structures of GSTPl gene reported from different laboretories have been identical, leading to the notion that the different GSTPl isoenzymes have distinctly specific metabolic activities to carcinogens. Some studies observed a different relation between the GSTPl polymorphism and an increased resk for oral, breast, colorectal, prostate and lung cancers. For example, the GSTPl 105Val allele was found to increase in patients with breast Cancer whereas the GSTPl 105He allele to increase with esophageal cancer. Regarding gastric cancer, only a few studies were conducted to investigate its association with GSTPl variants. Accordingly we described a case - control study to determine if this GSTPl poly-morphism influences suseceptibility to gastric cancer using a polymerase chain reaction(PCR) to detect variant forms of GSTPl, as well as the interaction between the polymorphism and environmental factor(anti -H. pylori immunoglobu-lin G(IgG) status) involved in gastric carcinogenensis.Study ObjectiveTo analysis the distribution of polymorphism of GSTPl in population in the northeast China and the relationship between the polymorphic BsmAI site in ex-tron 5 of glutathione - S - transferase PI ( GSTPl ) with susceptibility to gastric cancer and evaluate the combined effect between genetic polymorphic of GSTPl and H. pylori infection on gastric cancer.Study MethodsPolymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were performed to analyze the genotype GSTPl polymorphisms in exon 5 (IlelO5Val). Blood samples were taken from 1,612 subjects in the Northeast China, including high and low risk areas of gastric cancer. Subjects underwent H. pylori/IgG examination by serology.Study ResultsAmong subjects in the Northeast China, 22% were the GSTPl 105A/G variant allele frequencies, which is siginificantly different from western people. The difference in GSTPl allele gene distribution between the area of high incidence of gastric cancer(23% ) and low incidence (20% ) has statistical significance. Further analysis combinedthe sex effect of the polymorphisms, the proportion of GSTPl variant allele gene was significantly higher in the men than in the women(24% vs 20% ) , specially in Zhuanghe region, a high risk area of gastric cancer in the north of China (X2 =5.100, P <0.05);The frequency of GSTPl Val/Val genotypes was statistically higher in thegastric cancer group compared with the non - gastric cancer population. The a-nalysis showed a statistically significant 1. 587 - fold increase in gastric cancer risk associated with GSTPl V105 allele gene;Moreover, there was a statistically significant interaction (odd ratio, 17. 571;95% confidence interval, 6.207-49. 742) between GSTPl Val/Val genotype and Hp/IgG difference positive status;Study ConclusionOur results indicate that the distribution of GSTPl polymorphism has statistical significance with sexual and geOgraphic difference. The individuals with GSTPl V105 allele gene show an increased risk in suffering from gastric cancer. Association of the GSTPl ( Val/Val) genotype with Hp/IgG positive factor could significantly increase gastric cancer risk assessment.