A Study Of Relationship Between RAS-RAF-ERK, PI3K-PTEN-AKT And Colorectal Cancer And Its Liver Metastasis

Objective:To analyze the relationship between KRAS,BRAF, PI3KCA, PTEN on RAS-RAF-ERK,PI3K-PTEN-AKT and clinicopathological characters of liver metastasis and survival of colorectal cancer. Method:From 2001 to 2008,300 patients who underwent colorectal cancer surgery in the Department of General Surgery of Zhongshan Hospital Fudan University were assigned to research groups.According to the diagnosis and follow-up, we divided them into three groups of 100cases in each group, which were colorectal cancer without liver metastasis, synchronous liver metastasis, and metachronous liver metastasis. We detected the status of KRAS, BRAF, PI3KCA and PTEN in primary tumor tissues by Pyrosequencing. Then we analyzed the relationship between them and pathologicalcharacters of primary tumors, liver metastasis and survival prognosis, by univariate Chi-square test, multivariate Logistic regression, Cox proportional hazard model analysis. Results:In 300 cases, KRAS mutation rate was 40%(120/300), BRAF mutation rate was 13.6%(41/300), PI3KCA mutation rate was 25%(75/300) and PTEN mutation rate was 18.7%(56/300).RAS-RAF-ERK activation was 145, PI3K-PTEN-AKT activation was 115(38.3%),while the activation of the two pathways were 59(19.7%).Among the groups of no liver metastasis, synchronous liver metastasis, metachronous liver metastasis, KRAS mutation rate was 30.3%, 31.1%,38.5%;BRAF mutation rate was 29.3%,29.3%,41.5%;PI3KCA mutation rate was 29.3%,40%,30.7%, PTEN mutation rate was 30.4%,37.5%,32.1%.1,By single factor Chi-square test, KRAS gene mutation was associated with lymph node metastasis (P=0.047), BRAF gene mutations was associated with the degree of differentiation (p=0.010), PI3KCA gene mutation was associated with ulcers infiltrative tumor (p=0.026), PTEN mutation was associated with ulcer infiltrating tumor and vessel invasion (p=0.017, p=0.003).2,Synchronous liver metastasis was related to the both activation of RAS-RAF-ERK and PI3K-PTEN-AKT patway, while metachronous liver metastasis was related to the activation of PI3K-PTEN-AKT pathway while RAS-RAF-ERK unactivted (p=0.025).3,By Multiple regression analysis, the synchronous liver metastasis was related to less than 65 years old, poor differentition, lymph nodes stage and both activation of two cell signaling pathway(p=0.021,HR=3.544,95%CI[1.210-10.377]),while the metachronous liver metastasis was related to male, poor differentiation, lymph node stage, PTEN gene mutation(p=0.043,HR=1.819,95%CI[1.451-2.488]).4, The 1,3, 5-year survival rate in BRAF gene mutation cases and activation of RAS-RAF-ERK pathway was 63%,39%,34%(p=0.025) and 67%,46%,37%(p=0.037), which had statistical significance.5,Application of Cox proportional hazards model to analyze the prognosis of colorectal cancer, we found that less than 65 years old, tumor infiltrating through serosa, lymph node stage, BRAF gene mutations(p=0.048, HR=1.320,95%CI=[1.095-2.310])were the risk factors of postoperative death in non-liver metastasis group. Tumor infiltrating through serosa and BRAF gene mutations (p=0.016,HR=2.107,95%CI=[1.506～4.421])were the risk factors of postoperative death in synchronous liver metastasis group. Poor differentiation, lymph node stage, PI3KCA gene mutations (p=0.046, HR=1.460, 95%CI=[1.188～8.128])were the risk factors of postoperative death in metachronous liver metastasis group. Conclusion:Detecting the status of KRAS, BRAF, PI3KCA, PTEN and analysing the cell signaling pathway in colorectal cancer can predict the liver metastasis and survival prognosis.