| 1Background and PurposeIn the western countries, the incidence of eophagogastric junction adenocarcinoma (AEG) including gastric cardia adenocarcinoma (GCA) is rising significantly during the past decades. Although the epidemiological data of GCA in China is not profound as in esophageal cancer (EC), an increasing tendency for GCA has been observed in China, especially in municipal regions. The prognosis for GCA is very poor. Overall5-year survival rate for GCA is only20%-30%. Interestingly,5-year survival rate GCA patients at early stage could be as high as95%. Frequent lymph node metastasis has been demonstrated as one of key issues for poor survival in GCA. The numbers of total dissected lymph nodes and metastatic lymph nodes have been well documented as independent pronostic indicator for EC. However, in GCA, it is largely unknown for optimal extent of lymph node dissection and prognosis. Clinical follow-up has clearly showed that the GCA patients with metastatic lymph nodes have different survival time. Obviously, there may be different molecular mechanisms involved. Our recent genome wide association study (GWAS) has identified18promising single nucleotide polymorphism (SNP) loci, including rs11134032located at Iroquois home box1(IRX1), which are related with high risk for both EC and GCA. IRX1, a kind of tumor suppressor gene, has been demonstrated to be related with cell proliferation and invasion. Thus, the present study was undertaken to characterize the optimal extent of dissected lymph node number and survival and IRX1polymorphism variations in GCA.2Materials and Methods2.1PatientsPart I:All the information of8204patients with GCA came from database in Henna Key Laboratory for Esophageal Cancer Research. The patients mainly came from Taiwan Mountain region, the high incidence areas for GCA at the junction of Henna, Shania, Heber provinces. All the patients were treated by surgery alone with clear postoperative pathological examination reports from1976to2010. Part II:Of the8204GCA patients in Part Ⅰ,655cases were further performed Tag man analysis for rs11134032locus at IRX1.2.2Follow-upAll the data were collected from the large-scale follow-up and questionnaire survey on the patients in high-incidence area for GCA.2250GCA patients were finally enrolled in this study based on the records of the survival and clinical information. Among the2250patients with GCA in Part Ⅰ,95failed to be followed-up with the follow up rate of87.1%. Among the655patients with GWAS in Part Ⅱ,236failed to be followed-up with the follow up rate of63.9%.2.3StatisticsStatistical package of social science (SPSS)18.0was used to analysis all the data. We used Chi-square(χ2) test to analysis the relationship between gender, age, T stage, differentiation, N stage and lymph node metastasis rate; the relationship between metastatic lymph node ratio(MLR) and the allele and genotype frequencies of IRX1gene of rs11134032; the distribution of IRX1gene weather meet Hardy-Weinberg equilibrium(HWE) or not. Single variable logistic regression was used to analysis the relationship between the number of dissected lymph nodes, differentiation and lymph node metastasis rate. Kaplan-Meier was used to analysis the relationship between the number of dissected lymph nodes and positive lymph nodes and genotype frequencies of IRX1gene of rs11134032and survival. Cox proportional hazards modeling was used to analysis the relationship between risk factors and survival of patients with GCA. P<0.05was considered as significant.3Results3.1Relation between clinic pathological characteristics and lymph node metastasis rateThe difference between distribution of gender and age and lymph node metastasis rate was not significant(P>0.05). The difference between differentiation and T stage and lymph node metastasis rate was significant (P<0.05). The poorer the differentiation, the lymph node metastasis rate was higher. The higher T stage, the lymph node metastasis rate was higher. The difference between the number of dissected lymph nodes and the lymph node metastasis rate was significant (P<0.05). The more number of dissected lymph nodes, the lymph node metastasis rate was higher.3.2Relation between different number of dissected lymph nodes with node-positive/negative and survival is significant (P<0.05).The difference between different number of dissected lymph nodes with node-positive and survival The order of survival rate of these four group from high to low was≥10,7-9,4-6and1-3. The difference between the dissected lymph nodes number1-2,3-4,5-6, and≥7with node-negative and survival was not significant (P=0.166).3.3Relation between the positive number of lymph nodes and survival The difference between the four different number of positive lymph nodes and survival was significant (P<0.01). The more number of positive lymph nodes, the survival was poorer.3.4Relation between metastatic lymph node ratio and survivalThe difference between the four group with different metastatic lymph node ratio0-30%,31-60%,61-90%and91-100%was significant (P<0.01). The higher metastatic lymph node ratio, the survival was poorer.3.5Prognosis factorsMultivariate Cox proportional hazards regression analysis indicated that differentiation, T stage, N stage and the number of dissected lymph nodes predicted for death.3.6HWE testThe observed value and predictive value of rs11134032locus of IRX1gene genotyping after HWE test were good.3.7Relation between the allele and genotype frequencies of IRX1gene of rs11134032and clinic pathological characteristicsThe difference between the distribution of gender and age and the allele and genotype frequencies of IRX1gene of rs11134032was not significant(P>0.05). The difference between the distribution of differentiation, T stage and clinical stage and the allele and genotype frequencies of IRX1gene of rs11134032was not significant(P>0.05).3.8Relation between the allele and genotype frequencies of IRX1gene of rs11134032and node-positive/negative patients The difference between the distribution of node-positive/negative patients and genotype frequencies of IRX1gene of rs11134032was significant (P=0.02). The difference between the distribution of node-positive/negative patients and the allele frequencies of IRX1gene of rs11134032was not significant (P=0.056)3.9Relation between the allele and genotype frequencies of IRX1gene of rs11134032and metastatic lymph node ratioThe difference between metastatic lymph node ratio≤20%and>20%and the allele and genotype frequencies of IRX1gene of rs11134032were significant (P=0.032; P=0.001)3.10Relation between the allele and genotype frequencies of IRX1gene of rs11134032and survivalThe different survival curve between the genotype of IRX1gene of CC/CT and TT was significant (P=0.005). The survival curve of genotype of CC/CT was better than TT.4Conclusions4.1The metastatic lymph node is the one of the key issues for GCA prognosis, and the optimal extent of lymph node dissection and prognosis depends on lymph node metastatic status;4.2The CC/CT genotype polymorphic variation at rs11134032locus within IRX1gene may be an important molecular candidate for GCA prognosis. |
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