| Background:As a common malignant tumor of the digestive system, colorectal cancer remains the fourth leading cause of cancer-related mortality all over the world. It was also the third most popular disease. In China, there are about150000new cases and90000death cases, leading the fifth cause of common malignant tumor incidence and the sixth cause of mortality. In recent years, with the change of food structure and lifestyle, the incidence and mortality rate of colorectal cancer has been on the rise year by year. As a process of multiple factors and stages, colorectal cancer is the result of joint action of environmental and genetic factors. Although stage is the best available clinical measure of tumor aggression and prognosis, there are clearly important differences even within the same tumor stage. Single nucleotide polymorphisms, which are common variations in the human genome, could be suitable molecular markers for locating and identifying genes related to specific diseases. Previous studies have indicated various polymorphims involved in the invasion, development, and prognosis of gastrointestinal tumors. Mammalian target of raparnycin (mTOR) products are concerned as two distinct complexes (i.e., mTORCl and mTORC2) with different sensitivity. As a key component of PI3K/Akt/mTOR pathway, mTOR is closely relevant to capital cellular processes such as cell growth, proliferation, metabolism, migration, angiogenesis, and apoptosis. In recent years, studies have found that mTOR dysregulation often appears in various kinds of cancers during the carcinogenesis and deterioration. But there are few study on the relationship between polymorphisms in mTOR and prognosis of colorectal cancer.Objective:In this study, the relevance of polymorphisms (rs2295080) in mTOR and prognosis of colorectal cancer patients were analyzed, and the relationship between clinical features and prognosis of colorectal cancer patients were assessed as well. Teasting for the polymorphism might help identifying patient subgroups at high risk for poor disease outcome, thereby helping to refine therapeutic decisions in the treatment of colorectal cancer.Method:1. Sample collection and patients following-up:488colorectal cancer patients who were diagnosed by colonoscopy and histopathological methodand underwent tumor resection in the Department of Surgical Oncology at the Second Affiliated Hospital of Zhejiang University School of Medicine from February2011to October2013were enrolled. Blood samples for experiment were collected from patients before operation. The patients’clinical characteristics were accurately recorded, and the survival status of post-operation patients were followed up by phones. The follow-up deadline was June2014. 2. DNA extraction and sequencing:The DNA was extracted with DNA purification kit from blood samples. The target gene of qualified DNA samples were then confirmed by TaqMan method using real-time PCR reaction system.3. Statistical analysis:All analysis were performed by SPSS17.0software with two-sided P values, P<0.05was considered statistically significance. Kaplan-Meier method was used to draw survival curves and its significance was tested by Log-Rank method. Factors related to the prognosis were analyzed by Cox regression model. P-value, hazard ratios (HR) and95%confidence interval (CI) were calculated.Results:1、There was no significant association between rs2295080and survival of colorectal cancer. When the primary location of the tumor was considered during the analysis, rs2295080showed a significant prognostic impact. In the colon cancer subgroup, survival in patients with the GG genotype was dramatically different (P=0.018, HR=3.07,95%CI=1.15-8.22), compared with patients with the TG/TT genotypes in the recessive model. The risk effect was more pronounced among patients with moderate differentiated (P=0.008, HR=3.74), no lymph node metastasis (<0.001,11.87), combined TNM stage Ⅱ (<0.001,14.74). For rectal cancer patients, rs2295080TG/GG genotypes had better prognosis (P=0.049, HR=0.48,95%CI=0.23-0.99), compared with the TT genotype in the dominant model. The risk effect was more pronounced among patients with no distant metastasis (P=0.011, HR=0.28) and TNM stage III (0.019,0.21).2、 The univariate survival analysis showed that clinical characteristics, such as gender, age, degree of differentiation, invasion depth were no relevance with the prognosis of colon cancer patients, and lymph node metastasis (P<0.001), distant metastasis (P=0.001) and clinical stage (P<0.001) were the related factors for prognosis of patients with colon cancer. For patients with rectal cancer, gender, age and degree of differentiation had no significant correlation with the prognosis, and invasion depth (P<0.001), lymph node metastasis (P<0.001), distant metastasis (P<0.001) and clinical stage (P<0.001) were the related factors.3、 A multivariate stepwise Cox regression model was performed to evaluate the correlation between variables including the selected patients’characteristics, clinical features, SNP rs2295080and rectal cancer survival. Three variables (e.g., TNM stage, distance metastasis, and rs2295080) were included in the regression model (P=0.006for TNM stage, P=0.001for distance metastasis, and P=0.039for rs2295080). As for colon cancer group, two variables (e.g., Lymph node metastasis, and rs2295080) were included in the regression model (P<0.001for Lymph node metastasis, and P=0.021for rs2295080).Conclusions:1. The polymorphisms of rs2295080was an independent factor for prognosis of colon and rectal cancer patients. The patients carrying rs2295080GG genotype survived for a shorter time than those with the TG/TT genotypes in the colon cancer subgroup. For rectal cancer patients, rs2295080TG/GG genotypes had better prognosis compared with the TT genotype. The polymorphism of mTOR is expected to become a new molecular marker to diagnosis of colorectal cancer, and guide clinical treatment.2, Lymph node metastasis was an independent factor for prognosis of colon cancer patients. The prognosis of patients with no lymph node metastasis was superior to lymph node metastasis. Clinical stage and distance metastasis were independent factors for prognosis of retal cancer patients. The prognosis of patients with stage Ⅰ+Ⅱ was superior to stage Ⅲ+Ⅳ. The length of survival of patients with no distance metastasis was longer than that of patients with distance metastasis. |
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