| 1. Background and ObjectiveEsophageal carcinoma is one of the most common six malignant tumors in the world. It is late founded and with poorly prognosis. Its five-year survival rate of patients with middle and advanced cancer is only about10%. Lymph node metastasis is one of the most important factors affecting the long-term survival in patients with esophageal cancer after surgical resection which is the top preferred treatment for esophageal carcinoma. Some reports have shown that the overall five-year survival rate of patients without metastasis after surgical resection is about70%-92%, while rate of patients with metastases is only18%-47%. This paper mainly discusses the number of lymph node resection and metastasis on prognosis of esophageal cancer.As we know, prevention, early detection and treatment are the key issues to reduce the mortality for esophageal carcinoma patients. However, since the exact factors for esophageal cancer have not been well understood and the molecular mechanisms of development are not clear, the biological control strategies and indicators which have strong specificity and high sensitivity on the early diagnosis and screening are lacked. At the same time, its first and secondary prevention measures and effectives are poor which makes the situation worse. Based on our previous genome-wide association study, we aim to find more effective biomarkers for screening and early warning in high-risk population groups.Therefore, this paper aims to discuss the relationship between clinicopathological features in esophageal cancer patients with lymph node metastasis and the SNP variation in patients’certain genetic loci. Meanwhile, we try to look for the molecular characteristics related to the genetic and metastasis aspects of the patients which can be used for quickly testment, and expect forming adequate coping strategies for various clinical manifestations and prognosis of patients.2. Materials and Methods2.1Patients2.1.1Lymph node metastasis and prognosisWe selected8,924underwent surgery patients with clear record of lymph node specimen from1976to2002. Of these8,924cases, there were5,428males with a mean age of55.23±9.02, and3,496females with a mean age of55.35±8.70. The ratio of male to female was1.55:1, and the ages were range20to98. Patients, who were mainly from the Taihang Mountains esophageal carcinoma high incidence on the junction of Henan, Shanxi, Hebei provinces, were all treated by surgery alone with clear postoperative pathological examination reports.2.1.2Lymph node metastasis and rs13042395locus within C20orf54geneOf the2,616cases, there were1,663males with a mean age of59.25±8.07and953females with a mean age of60.37±7.87. The ratio of male to female was1.75:1. The minimum age was26and the maximum age was81. The average ages were55.27±8.90years and the median age was55. Stating at the end of2008and ending at the end of2010, the patients were mainly from the hospitals, including those in Henan, Shanxi, Hebei, Shandong, Sichuan, Guangdong, Fujian, Beijing, Jiangsu, Shaanxi, Ningxia and other provinces and cities, and were diagnosed through gastroscopy by at least two gastroenterologists. All of the cases were comformed through pathology examination by pathologists.2.2Statistical methodsSeveral factors that can impact lymph node metastasis or prognosis were selected.18SNP loci genotypes measured by the GWAS were selected and its relevant data were quantified and assigned. The survival time was calculated in years; the correlation between the single factor and lymph node metastasis or the SNP loci was analysised by Chi-square test; the relationship between multi-factor and lymph node metastasis was analysised by binary logistic regression analysis; the influences of single factor and genetic loci on the prognosis was studied by the Kaplan-Meier survival curves and its statistically significant was tested by Log-Rank test; Cox proportional hazards model in multivariate analysis was used to eliminate the mutual interactions of multiple variables, and significant risk factors to survival were filtered out; cumulative survival rate was studied by Life tables method.3. Results3.1Lymph node metastasis and clinical pathological data analysis3.1.1Relationship between lymph node with or without metastases and clinical indicators of each single factorChi-square test result showed that there were significant differences (P<0.05) in lymph node with or without metastasis and patients’gender, family history, high-and low-incidence areas, tumor location, tumor length, degree of differentiation, depth of invasion, and increasing lymph node dissection increased the risk of lymph node metastasis (P<0.05), on the other hand, there were not significant difference (P>0.05) in age, blood type, smoking history, alcohol consumption history.3.1.2Multi-factor analysis on lymph node with or without metastasisLymph node with or without metastasis related indicators were acquired statistically by univariate analysis, after using multivariate logistic binary regression to eliminate the interaction between several relevant factors, then independent risk factors of lymph node metastasis were acquired. The numbers of lymph node dissection, T stage (depth of infiltration), degree of differentiation, tumor location, high-and low-incidence areas were all statistically significant (P<0.05).3.1.3Relationship between the number of lymph node dissection, metastasis and the5-year and10-year survival rateLife table analysis showed that accompanied by removal of the increasing number of lymph nodes, the5-year and10-year survival rate was gradually increased (P<0.05); along with the increase in the number of lymph node metastasis, the 5-year survival and10-year survival rate followed by decreased (P<0.05).3.1.4Relationship between the groups with different numbers of lymph node dissection, metastasis and the survivalGroups were in accordance with the lymph node dissection number of1-6,7-12,≥13, the median survival time by3.61years,5.43years,7.89years (P<0.05). Groups were in accordance with the lymph node metastasis number of0,1-2,3-6,≥7, the median survival time were9.72years,2.67years,1.95years,1.92years (P<0.05).3.1.5Relationship between the number of lymph node dissection with metastasis and survivalLog-Rank test and Life table analysis show that groups are in accordance with the lymph node specimens number of1-12and≥13, the5-year survival respectively are25%,49%, and the10-year survival rates are18%,25%(P<0.05).3.1.6Relationship between the number of lymph node dissection without metastasis and survivalLog-Rank test and Life table analysis showed that groups were in accordance with the lymph node specimens number of1-6,7-13,>14grouping, the5-year survival rate were51%,69%,61%, and the10-year survival rate wre40%,58%,54%(P<0.05). Survivals in two groups of1-6,7-13were increased, but the≥14group survivals began to decline and its survival curves was just between former two groups.3.1.7Survival affected analysis of single independent factor and comprehensive multi-factorsWe picked out independent risk factors of gender, lymph node with or without resection, depth of invasion, degree of differentiation to analyse the multivariate Cox proportional hazards model. The results suggested that with or without lymph node metastases had a significant effect on survival which HR (95%CI) was1.973(1.727-2.254). For overall patients, the increasing number of lymph node dissection could prolong survival. Compared to1-6group survival, HR of group≥13was0.574(0.427-0.771). The results suggested that lymph node without metastasis, female, remove more than13lymph nodes were protective factors on prognosis (P<0.05); while poor-differentiated, increased depth of invasion could significantly decrease survival (P<0.05).3.2Analysis of lymph node metastasis, SNPs loci and other clinicopathological information3.2.1Relationship between lymph node metastasis and SNPs lociAfter the Chi-square test of genotyping with or without lymph nodes metastases of18sites which had been found had been done, the results suggested that the genotype distribution of rs13042395locus within C20orf54gene was related to lymph node metastasis (P<0.05). Logistic binary regression testing confirmed that compared with CC genotype, TT genotype is one of risk factors for lymph nodes metastases (P<0.05) and its HR is1.637(1.089-2.461).3.2.2Relationship between rs13042395locus within C20orf54gene and patients routine data and clinicopathological parameters.After the Chi-square testment of rs13042395locus genetic polymorphism and patients routine data and clinicopathological parameters in esophageal cancer patients had been done, the results showed that the genotype distribution had a notable correlation with patients family histories (P<0.05). The distribution of TT genotype was wider in patients from low incidence areas or with negative family histories, suggesting that the TT genotype might be connected with lymph nodes metastases molecular mechanism in those patients. The genetic polymorphism of rs13042395locus within C20orf54gene had no notable correlation with gender, age, blood type, smoking history, drinking history, degree of differentiation, depth of invasion, clinical stage, tumor location, tumor length, and lymph node metastasis of esophageal cancer patients.3.2.3Relationship between rs13042395locus within C20orf54gene and prognosisIn768patients, there were414cases of CC type,294cases of CT type and60cases of TT type. Log-Rank test showed that the difference between the survival and the diversities of three genotypes distribution on the rs13042395locus wass not statistically significant (χ2=2.173, P=0.337).4. Conclusions 4.1Lymph node metastasis was one of critical factors in the prognosis of patients with esophageal cancer, and the relationship between the number of lymph nodes dissection and prognosis depended on lymph nodes metastases.4.2The polymorphic variation of TT genotype on rs13042395locus within C20orf54gene was significantly related to lymph node metastasis in patients with esophageal cancer. And this kind of variation might be connected with lymph node metastases molecular mechanism in those patients with negative family histores or low incidence areas. |
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