| Although the incidence rate of gastric cancer was declined in recent years, it still remains the fourth most common cancer and the second cause for cancer related deaths around the world. Gastric cancer is also one of the most common cancers and remains a significant cancer burden in China, as a result of the increasing population base and elongation of gastric cancer patients'life expectancy.The exact mechanism about gastric cancer is still unclear. The gastric carcinogenesis is a complex process with multiple factors and steps, and is commonly considered as the combination of environment exposures and genetics. Abundant classical epidemiology studies have discovered some risk factors of gastric cancer, including H.pylori infection, N-nitroso-compound, salty food, deficiency of nutriment, smoking and drinking. Especially for H.pylori infection, since H.pylori has been defined as a Group I human carcinogen by WHO.However, although different individuals are surrounded by the same environment exposures, only minority develops gastric cancer. For instance, the worldwide H.pylori infection rate exceeds 50%, but only 1% develops gastric cancer. This indicates that different individuals have different susceptibility to environment exposures, which are considered to be determined by genetics. Nevertheless, the exact genetic mechanism is not clear.Over the last several years, as a powerful method to investigate the genetic determinants of complex diseases, genome-wide association studies (GWAS) have successfully identified hundreds of genetic markers that are related to the susceptibility of diseases. One GWAS identified two Single Nucleotide Polymorphism (SNP) (rs4072037 at 1q22 and rs2274223 at 10q23) were significantly associated with risk of gastric cancer and esophageal squamous cell carcinoma (ESCC) in Chinese population in 2010. In the same period, another GWAS of ESCC in Chinese population identified the same SNP of rs2274223 at 10q23 as well as a new SNP of rs13042395 at 20p13 for ESCC susceptibility. Both of these two SNPs were also associated with risk of gastric cardia cancer.In addition, some genetic variants identified by GWAS are not only associated with one kind of cancer, but also are involved in susceptibility of various tumors. Variants on chromosome 8q24 is not only significantly associated with risk of prostate cancer, but also a susceptible one shared for multiple tumors, including breast, colorectal, ovarian, renal, thyroid and laryngic cancers. These findings indicated that chromosome 8q24 might be the susceptible region related to multiple tumors with similar biological mechanisms.Thus, for the repeatability of result of GWAS in different population, we performed a case-control study to detect the association of genetic variants at chromosome 1q22, 10q23 and 20p13 with gastric cancer risk in Chinese Jiangsu population. Besides, another case-control study was also conducted to investigate whether genetic variants at chromosome 8q24 were associated with risk of gastric caner in Chinese population. The results of this study will be helpful for confirming the results of GWAS in other independent population, determining the genetic factors of gastric cancer and illustrating the susceptibility mechanism in gastric cancer.Part I: Association Study between Genetic Variants at 1q22, 10q23 and 20p13 and the Risk of Gastric CancerTwo recent genome-wide association studies (GWAS) reported significant associations of genetic variants at 1q22, 10q23 and 20p13 with gastric cancer (GC) risk in Chinese populations. However, these findings have not been confirmed in other independent studies. Here, we performed an independent case-control study in a Chinese population by genotyping three loci (rs4072037A>G at 1q22, rs2274223A>G at 10q23 and rs13042395C>T at 20p13) in 1,681 GC cases and 1,858 controls. We found that rs4072037 at 1q22 and rs2274223 at 10q23 were significantly associated with risk of GC with per allele odds ratio (OR) of 0.72 [95% confidence interval (95%CI): 0.63-0.81; P = 2.98×10-7] and 1.42 (95%CI: 1.27-1.58; P = 9.68×10-10), respectively. In stratified analyses, the association was more prominent for rs2274223 in female (OR = 1.86, 95%CI: 1.49-2.32) and gastric cardia cancer (GCA) (OR = 1.71, 95%CI: 1.49-1.95). Furthermore, we combined the two SNPs to evaluate the joint effect and found that the GC risk significantly increased with the number of risk allele increasing with a trend P value of 6.66×10-16, and individuals with 4 risk alleles had a 3.28-fold (95%CI: 1.75-6.13) risk of GC compared with those having no risk alleles; (4) however, no significant association was detected between rs13042395 at 20p13 and GC risk (OR = 1.04, 95%CI: 0.94-1.15; P = 0.452). In conclusion, our results indicate that genetic variants at 1q22 and 10q23 but not 20p13 may serve as candidate markers for GC susceptibility in the Chinese population.Part II: Association Study between Chromosome 8q24 variants and the Risk of Gastric CancerCancer genome-wide association studies have identified genetic variants on chromosome 8q24 associated with risk of multiple cancers including prostate, colorectal and breast, suggesting that the chromosome 8q24 may be a multi-cancer susceptible region. To test the hypothesis that genetic variants in this region were also associated with susceptibility of gastric cancer (GC), we conducted an independent case-control study including 1053 GC cases and 1100 cancer-free controls in a Chinese population by genotyping three loci (rs6983267 G>T, rs13281615 G>A and rs445114 C>T) defining two multiple cancer susceptible regions at 8q24. Although the associations between the above 3 SNPs and risk of GC were not statistically significant among overall study subjects, we found that the variant allele of rs6983267 (G) was associated with a significantly increased risk of GC among alcohol drinkers (OR=1.32, 95% CI=1.03-1.68) and among gastric cardia cancer cases (OR=1.17, 95% CI=1.00-1.36), respectively. In addition, the association of rs6983267 (G) with risk of gastric cardia cancer was more evident in alcohol drinkers (OR=1.59, 95% CI=1.15-2.18) with a significant multiplicative interaction (P = 0.02). However, none of the significant associations were observed between the SNPs rs13281615 (OR =1.04, 95% CI: 0.92-1.18) and rs445114 (OR =1.01, 95%CI: 0.90-1.14) and GC risk in overall or in subgroups. Our results indicate that genetic variant rs6983267 on chromosome 8q24 and alcohol drinking may jointly play a role in cardia gastric cancer development in Chinese population. |
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