The Combined Prediction Of P53,COX2,EGFR And Mm23 In The Post-operative Patients With Colorectal Carcinoma And Its Subgroup Analysis

The first part:The correlations between p53,COX2,EGFRand nm23 expression and PFS of the post-operative patients with colorectal carcinomaBackground:The incidence and mortality of colorectal cancer are increasing year by year,and there is still a lack of more accurate prognostic indicators.Objective:The aim of this study was to evaluate the correlations between p53,COX2,EGFR,nm23 expression and the progression free survival(PFS)of post-operative patients with colorectal carcinoma,and explore the optimal combination of predictors for tumor recurrence and metastasis in the post-operative patients with colorectal carcinoma.Methods:Immunohistochemistry was used to detect the expression of p53,COX2,EGFR and nm23 in 459 specimens from the patients with colorectal carcinoma in the Third Affiliated Hospital of Soochow University from March 2003 to July 2010.Kaplan-Meier estimates,Cox proportional hazard regression analyses were performed to analyze the influencing factors of the risk of tumor progression on the collected data.Results:Immunohistochemistry results showed that,in the patients with colorectal carcinoma,p53 expression accounted for 58.52%,COX2 expression accounted for 84.28%,EGFR expression accounted for 53.71%,nm23 expression accounted for 67.25%.TNM stage,pathological grade,EGFR and nm23 expression had statistical significance to the PFS of post-operative patients with colorectal carcinoma(P<0.05).EGFR expression was as a negative predictor,the median PFS of patients with EGFR high expression was 21.7months,and the median PFS of patients with low EGFR expression was 57.8 months(χ~2=20.880,P=0.001);nm23 expression was positive predictive factor for the prognosis of patients with colorectal carcinoma,the median PFS of patients with high nm23 expression was 37.7 months,and the median PFS was 21.4 months in the patients with low nm23expression(χ~2=7.364,P=0.007).Cox regression analysis revealed that patients with TNM stage I-II colorectal carcinoma vs.patients with TNM stage III-IV colorectal carcinoma,the latter is at higher risk of tumor progression(HR=1.604,95%CI:1.108-2.321,P=0.012),and TNM staging is an independent prognostic factor;Comparing with the patients with pathological grade I-II,patients with pathological grade III-IV had higher tumor progression risk(HR=1.521,95%CI:1.068-2.167,P=0.02);Comparing with the patients with low expression of EGFR,the patients with high EGFR expression were at higher risk of tumor progression(HR=1.667,95%CI:1.177-2.362,P=0.004);Comparing with the patients with high nm23 expression,the patients with nm23 low expression had a higher risk of tumor progression(HR=0.412,95%CI:0.288-0.591,P<0.001);the risk of tumor progression was higher in the patients with high EGFR expression and low nm23expression(HR=0.245,95%CI:0.142-0.426,P<0.001).Conclusion:There was no correlation between p53 and COX2 expression and PFS of the patients with colorectal carcinoma,it may be related to the occurrence of colorectal carcinoma.The expression of EGFR is a negative predictive factor for the prognosis of post-operative patients with colorectal carcinoma,and the nm23 expression is a positive predictive factor for predicting the prognosis of patients with colorectal carcinoma.EGFR high expression and nm23 low expression are more likely to be associated with a higher risk of tumor progression in colorectal cancer patients.EGFR and nm23 could be as a more effective combination predictor for the prognosis of patients with colorectal carcinoma.Detecting the expression of EGFR and nm23 in patients with colorectal carcinoma is of great significance in evaluating the risk of progression of colorectal carcinoma.The second part: Hierarchical investigating p53,COX2,EGFR,nm23 expression in colorectal carcinoma and its clinical significanceBackground: So far,TNM staging and pathological grading is still used to evaluate the risk of tumor progression,and the combination of the factors and some tumor markers can improve the accuracy of prognosis.However,it still needs to confirm if it is different that the expression of p53,COX2,EGFR and nm23 influence on PFS of patients with colorectal carcinoma in different TNM stages and pathological grades.Objective: The aim of this study was to evaluate the correlations between p53,COX2,EGFR,nm23 expression and the progression free survival(PFS)of post-operative patients with colorectal carcinoma,and explore the optimal combination of predictors for tumor recurrence and metastasis in the different TNM stages and pathological grades,and confirm if it is different that the expression of EGFR and nm23 influence on PFS of patients with colorectal carcinoma in different TNM stages and pathological grades.Methods: Immunohistochemistry was used to detect the expression of p53,COX2,EGFR and nm23 in 459 specimens from colorectal carcinoma patients.Hierarchical analyses were performed on the expression of EGFR and nm23 influence on PFS of patients with colorectal carcinoma in different TNM stages and pathological grades.Results: Hierarchical analysis showed that EGFR expression mainly affects the PFS of TNM stage I-II colorectal cancer patients,the median PFS was 33.5 months in the TNM stage I-II colorectal cancer patients with high EGFR expression patients;The median PFS of the TNM stage I-II colorectal cancer patients with low EGFR expression was 70.4 months(χ2=9.530,P=0.002);The median PFS was 19.2 months in the TNM III-IV colorectal cancer patients with high expression EGFR,the PFS of the TNM stage III-IV colorectal cancer patients with low EGFR expression was 37.9 months(χ2=7.97,P=0.005);EGFR expression mainly affects the PFS of pathological grade I-II colorectal cancer patients,themedian PFS of pathological grade I-II colorectal cancer patients with EGFR high expression was 28.4 months,the median PFS of pathological grade I-II colorectal cancer patients with low EGFR expression was 65.1 months(χ2=18.766,P<0.001).The median PFS was 19.6 months in pathological grade III-IV colorectal cancer patients with high EGFR expression,the median PFS in pathological grade III-IV colorectal cancer patients with low EGFR expression was 30.7 months(χ2=3.846,P=0.05);nm23 expression mainly affects the PFS of TNM stage III-IV colorecatal cancer patients.The median PFS was 47.3 months in TNM stage I-II colorectal cancer patients with nm23 high expression,the median PFS was 48.9 months in TNM stage I-II colorectal cancer patients with low nm23 expression(χ2=0.101,P=0.750);The median PFS was 28.8 months in TNM stage III-IV colorectal cancer patients with nm23 high expression,the median PFS was 14.7 months in TNM stage III-IV colorectal cancer patients with low nm23 expression(χ2=3.846,P=0.05);nm23 Expression mainly affects PFS of the pathological grade III-IV colorectal cancer patients,the median PFS was 40.4 months in pathological grade I-II colorectal cancer patients with high nm23 expression,and the median PFS was 35.9 months in pathological grade I-II colorectal cancer patients with low expression(χ2=1.102,P=0.294).The median PFS was 28.5 months in pathological grade III-IV colorectal cancer patients with high nm23 expression,the median PFS was 15.9 months in pathological grade III-IV colorectal cancer patients with low expression of nm23(χ2=7.699,P=0.006).Conclusion: It is different that the expression of EGFR and nm23 influence on PFS of patients with colorectal carcinoma in different TNM stages and pathological grades EGFR expression mainly affects the PFS of post-operative patients with colorectal carcinoma in TNM stage I-II and pathological grade I-II;The expression nm23 mainly affects the PFS of post-operative patients with colorectal carcinoma in TNM stage III-IV and pathological grade III-IV.The third part: Hierarchical investigating the expression of EGFR and nm23 in rectal carcinoma and its impacts on the therapeutic effects of operation and chemotherapyBackground: Surgery and chemotherapy are the important approach for the treatment of rectal carcinoma,but the recurrence and metastasis after surgery is still the important cause of death for the patients with rectal carcinoma.How to improve the curative effect,it is a difficult problem we are facing.At present,the prognosis of patients with tumor is more accurate because of the clinical application of some tumor markers,it is of great significance to improve the curative effect.Objective: The aim of this study was to evaluate the predictive value of EGFR and nm23 expression and impact on the therapeutic effect,especially operation and chemotherapy,in post-operation patients with rectal carcinoma.It is important to understand the clinical significance.Methods: The expressions of EGFR and nm23 in 243 specimens of rectal carcinoma tissues were detected by immunohistochemistry,other clinical materials were recorded,and patients were followed up for more than five years.Kaplan-Meier estimates,Cox proportional hazard regression and hierarchical analyses were employed to assess the correlation between the expression of EGFR and nm23 in rectal carcinoma and the progression free survival(PFS)of patients with rectal carcinoma,and impact on the therapeutic effect of surgery and chemotherapy.Results: Immunohistochemical staining showed that EGFR and nm23 are expressed proportionately in rectal cancer tissues.EGFR expression accounted for 51.85%(151/243),nm23 expression accounted for 66.26%(161/243).Kaplan-Meier showed that EGFR expression is negatively related to the PFS of the post-operative patients,Median PFS was 21.0 months in the patients with high EGFR expression,and Median PFS was 37.8 months in the patients with low EGFR expression(χ2=8.687,P=0.003);nm23 expression ispositively associated with the PFS of the post-operative patients,Median PFS was 35.4 months in the patients with high nm23 expression,and Median PFS was 13.4 months in the patients with low nm23 expression(χ2=15.593,P=0.001);Median PFS was longer in the patients with low EGFR expression and high nm23 expression(Median PFS=62.9 months,χ2=18.227,P<0.001).Cox regression analysis revealed that comparing with post-Dixon patients,post-Hartman and mile’s patients were at higher risk of tumor progression through univariate analysis(HR=1.747,95% CI: 1.270-2.405,P=0.001)and multivariate analysis(HR=1.773,95% CI: 1.286-2.446,P<0.001).Comparing with the patients treated with FOLFOX4 chemotherapy,the patients treated with non-FOLFOX4 chemotherapy were at higher risk of tumor progression,univariate analysis(HR=1.690,95% CI: 1.226-2.329,P=0.001)and multivariate analysis(HR=1.710,95% CI: 1.239-2.360,P=0.001).In univariate analysis,the patients with low EGFR expression and high nm23 expression vs.the patients with high EGFR expression and low nm23 expression were associated with longer PFS(HR=2.290 95% CI: 1.548-3.387,P<0.001).Multivariate analysis(Cox)found that low EGFR expression and high nm23 expression was an independent combined predictor of longer PFS(HR=1.966 95% CI: 1.319-2.929,P=0.001).In addition,hierarchical analysis also suggested that post-Dixon operation patients with low EGFR expression and high nm23 expression had significantly longer survival time than the patients with high EGFR expression and low nm23 expression(Median PFS=62.9 months,χ2=9.170,P=0.003),and also were more sensitive to chemotherapy with FOLFOX4 regimen compared with other patients(Median PFS=61.1 months,χ2=8.218,P=0.004).Conclusion: EGFR and nm23 have predictive value for the prognosis of post-operative patients with rectal carcinoma and is an ideal combination of predictive factors.post-Dixon operation patients with low EGFR expression and high nm23 expression had significantly longer PFS than other patients,and patients treated with non-FOLFOX4 chemotherapy were at a higher risk of tumor progression;Post-Dixon operation patients with low EGFR expression and high nm23 expression had significantly longer PFS than other patients,and also were more sensitive to chemotherapy with FOLFOX4 regimen compared with other patients.The PFS is different in the patients treated with the different surgical methods and chemotherapy.The fourth part: Validating the correlations between EGFR and nm23 expression and the survival of the patients with colorectal carcinoma by TCGA dataBackground: TCGA data is the cancer genome atlas database that is established by the United States government,the purpose is to draw out the map of human genome variation of all cancers,find all oncogenes and tumor suppressor genes of small variation,understand the mechanism of the development of cancer cells at the genetic level,obtain new diagnostic and therapeutic methods on the basis of these data,finally work out a new strategy for tumor prevention and treatment.Objective: The TCGA database is one of the most influential and authoritative cancer gene databases in the world.Therefore,the results of our study were validated by using the data of EGFR and nm23 expression in colorectal cancer from TCGA database.Methods: Clinical data of 367 cases with colorectal carcinoma in TCGA database were collected,including 191 males and 176 females,aged 31-90 years with a median age of 65 years,The effects of EGFR and nm23 protein expression on the survival of the patients with colorectal carcinoma were analyzed by Kaplan-Meier,Cox regression and Hierarchical analysis.Results: The results show that the prognosis of patients with colorectal carcinoma and colorectal carcinoma TNM staging,the expression of EGFR and nm23 had statistical significance(P<0.05).there were significant correlation between OS and TNM stage,Median OS was 488 days in the patients with TNM stage I-II,Median OS was 409 days in the patients with TNM stage III-IV(χ2=6.699,P=0.01).EGFR expression is negatively related to the OS of the patients with colorectal carcinoma,Median OS was 409 days in the patients with high EGFR expression,and Median OS was 488 days in the patients with low EGFR expression(χ2=6.602,P=0.01);nm23 expression is positively associated with theOS of the patients with colorectal carcinoma,Median OS was 525 days in the patients with high nm23 expression,and Median OS was 399 days in the patients with low nm23 expression(χ2=7.631,P=0.006).Median OS was longer in the patients with low EGFR expression and high nm23 expression(Median OS=580 days,χ2=11.356,P=0.001).Cox regression analysis revealed that comparing with patients with stage I-II,the patients with stage III-IV were at higher risk of tumor progression through univariate analysis(HR =1.317,95% CI: 1.068-1.623,P=0.005)and multivariate analysis(HR=1.292,95% CI:1.047-1.595,P=0.017);Comparing with patients with low EGFR expression,the patients with high EGFR expression were at higher risk of tumor progression through univariate analysis(HR= 1.315,95% CI: 1.066-1.622,P= 0.011)and multivariate analysis(HR= 1.242,95% CI: 1.000-1.543,P=0.016);Comparing with patients with high nm23 expression,the patients with low nm23 expression were at higher risk of tumor progression through univariate analysis(HR = 0.744,95% CI: 0.603-0.919,P=0.006)and multivariate analysis(HR=0.802,95% CI: 0.644-0.998,P=0.048).In univariate analysis,the patients with low EGFR expression and high nm23 expression vs.the patients with high EGFR expression and low nm23 expression were associated with longer OS(HR=1.595 95% CI: 1.212-2.099,P=0.001).Multivariate analysis(Cox)found that low EGFR expression and high nm23 expression was an independent combined predictor of longer OS(HR=1.572 95% CI: 1.194-2.070,P=0.001).Hierarchical analysis showed that EGFR expression mainly affects the OS of TNM stage I-II colorectal carcinoma patients,the median OS was 464 days in the TNM stage I-II colorectal carcinoma patients with high EGFR expression patients;The median OS of the TNM stage I-II colorectal carcinoma patients with low EGFR expression was 525 days(χ2=3.264,P=0.05);The median OS was 362 days in the TNM III-IV colorectal carcinoma patients with high expression EGFR,the OS of the TNM stage III-IV colorectal carcinoma patients with low EGFR expression was 476 days(χ2=4.074,P=0.044).nm23 expression mainly affects the OS of TNM stage III-IV colorecatal carcinoma patients.The median OS was 580 days in TNM stage I-II colorectal carcinoma patients with nm23 high expression,the median OS was 412 days in TNM stage I-II colorectal carcinoma patients with low nm23 expression(χ2=2.570,P=0.0.109);The median OS was 479 months in TNM stage III-IV colorectal carcinoma patients with nm23 high expression,the median OS was 380 months in TNM stage III-IV colorectal carcinoma patients with low nm23 expression(χ2=3.941,P=0.047).Median OS was longer in theTNM stage I-II patients with low EGFR expression and high nm23 expression(the median OS=588 days,χ2=5.926,P=0.015).Conclusion: Verificating results of TCGA data show that EGFR and nm23 expression in patients with colorectal carcinoma are related to the survival,it is basically consistent with the results of our study;EGFR and nm23 is a combination of ideal predictors,and different in prognosis of different TNM staging of colorectal carcinoma,which can be used for colorectal cancer prognosis and guiding treatment.