Combined Detection Of JWA And P53Signaling Molecules Predicting The Prognosis Of Gastric Cancer And Facilitating Individualized Treatment

PURPOSE:There’s a high incidence of gastric cancer in China. Prognosis differents from patients to patients after standard surgery,while controversies still remain regarding the prognostic factors. The role of adjuvant therapy in gastric cancer has been controversial given the lack of significant survival benefit in many randomized studies and meta-analysis so far. Striking differences in prognosis among patients after standard surgery exist, indicating specific biomarkers are urgently needed. Herein, we chose resectable gastric cancer patiens to evaluate the effect of tumor-related protein JWA, p53and MDM2. Univariate and multivariate analysis were used to identify the prognosis and predictive value of each of them.METHODS:Expression of JWA, p53and MDM2were assessed by immunohistochemistry in three independent tissue microarrays, which were generated from paired tumoral and adjacent nontumoral gastric tissues collected from142gastric cancer patients in the training cohort and tumors taken from485and662patients in the two validation cohort group, respectively. The follow-up visiting was done by the co-operate hospital. Prognostic value of JWA, p53and MDM2and other clinicopathologic factors were evaluated in patients with surgery alone in three cohorts. The benefit for adjuvant chemotherapy compared with surgery alone was assessed by JWA, p53and MDM2expression status in two validation cohorts. All tests were performed at the0.05level of significances. Statistical analysis was completed using the SAS9.1.3statistic software.RESULTS:The distributions of demographic characteristics (age and gender) and the selected clinicopathologic variables (depth of invasion, lymph node metastasis, distant metastasis, TNM stage, tumor diameter and histological type) of patients between the two districts (Nantong and Yixing) were significantly different (all of P<0.05). JWA protein level was downregulated in gastric cancer lesions compared with adjacent noncancerous tissues in the training cohort. However, p53and MDM2protein levels were upregulated in cancer tissues compared with adjacent noncancerous tissues. JWA expression was significantly negative correlated with p53and MDM2expression not only in the nontumors taken from patients in the training cohort, but in the tumors taken from all three cohort patients (P≤0.001for all correlations). Low tumoral JWA or high p53and MDM2expression, which were associated with depth of invasion, presence of lymph node metastasis, high TNM stage and poor differentiation, was significantly correlated with shorter, overall survival (OS) in all three cohorts. However, neither nontumoral JWA nor p53and MDM2expression were associated with OS in the training cohort. Multivariate stepwise Cox regression analysis showed that JWA and p53were significantly associated with OS (JWA:HR=0.22,95%CI=0.13-0.36; p53:HR=6.92,95%CI=3.50-13.68) in the training cohort. However, MDM2was not associated with OS in training cohort (HR=1.91,95%CI=0.96-3.81). In the testing and validation cohorts, JWA, p53and MDM2expression were associated OS. It is shown that the patients received fluorouracil, leucovorin, and oxaliplatin (FLO) regimen was associated with improved survival compared with surgery alone (log-rank test, P=0.003), and this effect was similar in JWA negative group (HR=0.49;95%CI=0.31-0.76; Log-rank test, P=0.004) and MDM2positive group (HR=0.57;95%CI=0.37-0.89, Log-rank test, p=0.014). We also found the patients with p53high expression, who received fluorouracil, leucovorin, and cisplatin (FLP) regimen have a better survival (HR=1.91;95%CI=1.08-3.36, Log-rank test, p=0.003).CONCLUSIONS:1. The distributions of demographic characteristics and the selected clinicopathologic variables of patients between the two districts (Nantong and Yixing) were significantly different.2. JWA had lower expressions but p53and MDM2had higher expression in cancer tissue, which suggested they may play a important role in the process of tumer developing.3. It is showed that JWA level was negative relatived but p53and MDM2were positive relatived to the depth of tumor invasion, lymph node metastasis, distant metastasis and pathologic-TNM stage and differentiation.4. JWA, p53and MDM2may be the novel biomarkers for human gastric cancer progression and prognosis after gastrectomy as well as the potential therapeutic targets. Moreover, two of these biomarkers have better predictive effect than single biomarker. However, combination of three biomarkers did not show the better predictive effect than two of these biomarkers.5. Moreover, patients with low JWA or high MDM2in gastric tumors appear to benefit from postoperative adjuvant chemotherapy with FLO regimen to surgery alone, patients with high p53in gastric cancer tissues appear to benefit from FLP regimen.