The Associations Between SNPs Based On GWAS And Prognosis Of Gastric Cancer In A Chinese Population

As a common malignant tumor of the digestive system, gastric cancer remainsthe second leading cause of cancer-related mortality all over the world. It was also thethird most popular disease.2/3of all world cases were from Japan, South Korea andChina. Nearly40%of gastric cancer cases occur in China, which has been a highincidence area in past decades. The overall survival rate of gastric cancer isapproximately less than50%in China.According to Lauren staging, gastric cancer could be classified to diffuse andintestinal. As its main mechanisms still unknown, gastritis and mucosa intestinalmetaplasia were usual cause. But these happened in a few patients. Although stage isthe best available clinical measure of tumor aggression and prognosis, there areclearly important differences even within the same tumor stage. And most patients arediagnosed with advanced gastric cancer, and overall survival remains poor.Environmental factors were important in developoment and prevalence of gastriccancer. Only a few people got gastric cancer with a long time getting along with kindsof cancerigenic factors. Therefore, discovery of biomarkers and their application inconjunction with traditional cancer diagnosis, staging and prognosis could to a largeextent help improve early diagnosis and patient care. Single nucleotide polymorphisms, which are common variations in the humangenome, could be suitable molecular markers for locating and identifying genesrelated to specific diseases. Previous studies have indicated various polymorphimsinvolved in the invasion, development, and prognosis of gastric cancer. In recentyears, studies have focused on the detection of genetic variants that play roles in thedevelopment and progression of gastric cancer. And genome-wide association studieswere largely used in the susceptibility research of various cancers.We based on the results performed by previous studies, hypothesizing the PSCAand PLCE1were both associated to prognosis of gastric cancer. By a case-only studyof a large pupolation involved, we found that these results might provide new insightinto the incidence of gastric cardia cancers, although the role of these polymorphismsin the prognosis of gastric cancer is still unknown. Teasting for the presents of thesepolymorphisms might help identifying patient subgroups at high risk for poor diseaseoutcome, thereby helping to refine therapeutic decisions in the treatment of gastriccancer. Part Ⅰ. The associations between PSCA polymorphism and survival of gastriccancer in a Chinese populationObjective: Recent genome-wide association study (GWAS) has identified that theprostate stem cell antigen (PSCA) rs2294008is involving in regulating gastricepithelial-cell proliferation, influencing the risk of diffuse-type gastric cancer. Wehypothesized that PSCA rs2294008is also associated with gastric cancer survival.Methods: We genotyped PSCA rs2294008using TaqMan method in944patientswith surgically resected gastric cancer. The study patients were recruited from YixinPeople’s Hospital, Yixin City, China, between1999and2006. The different survivaltimes according to demographic and clinical information were estimated by using theKaplan-Meier method and assessed by using the Log-rank test. Mean survival timewas presented when the median survival time (MST) could not be calculated.Univariate or multivariate Cox regression analysis was fitted to estimate the crudehazard ratios (HRs), adjusted HRs and their95%confidence intervals (CIs), withadjustment for potential confounders. Cox stepwise regression analysis was alsoperformed to determine predictive factors for gastric cancer prognosis, with asignificance level of0.05for entering and0.10for removing the respectiveexplanatory variables. All analyses were done with SAS (version9.1; SAS Institute,Inc., Cary, NC) with two-sided P values.Results: There was no significant association between rs2294008and survival ofgastric cancer (Log-rank P=0.085for CT/TT versus CC). However, in thestratification analysis of histology, we found that rs2294008CT/TT genotypes wereassociated with significantly improved survival among diffuse-type gastric cancer[Log-rank P=0.025, hazard ratio (HR)=0.75,95%confidence interval (CI)=0.59-0.96], compared with the CC genotype. Moreover, this protective effect was more predominant for diffuse-type gastric cancer patients with tumor size>5cm anddistant metastasis.Conclusions: If validated in further studies, PSCA rs2294008could be usefulmarker of survival assessment and individualized clinical therapy for gastric cancer,particularly among the diffuse-type gastric cancer. Part Ⅱ. The associations between PLCE1polymorphism and survival of gastriccancer in a Chinese populationObjective: Two genome-wide association studies on gastric cancer shared apreviously unknown susceptible locus in PLCE1at10q23. We hypothesized that theSNP rs2274223A/G is associated with survival rate of gastric cancer.Methods: Genotyping and calculating methods are same with Part I.Results: We found that patients carrying PLCE1rs2274223AA genotype survived asignificantly shorter time than those carrying AG and GG genotypes (Log-rank P=0.046). This significance enhanced in dominant model (AA vs. AG/GG, Log-rank P=0.014). Multivariate Cox regression analyses showed that the AG/GG genotypeswas associated with a decreased risk of death for gastric cancer (adjusted HR=0.79,95%CI=0.65-0.95), and this protective effect was more significant among patientsof tumor size>5cm (HR=0.75,95%CI=0.56-0.99), diffuse-type gastric cancer(HR=0.77,95%CI=0.61-0.98), T3depth of invasion (HR=0.68,95%CI=0.53-0.86), lymph node metastasis (HR=0.74,95%CI=0.59-0.93), no distantmetastasis (HR=0.81,95%CI=0.66-0.99), and TNM stage III (HR=0.63,95%CI=0.48-0.83).Conclusions: Our findings showed that the PLCE1SNP rs2274223was associatedwith significantly improved survival of gastric cancer in a Chinese population.Further functional studies were needed to validate our results.