Upregulation of c-mesenchymal epithelial transition expression and RAS mutations are associated with late lung metastasis and poor prognosis in colorectal carcinoma

Abstract

The present study aimed to investigate whether c-mesenchymal epithelial transition factor (C-MET) overexpression combined with RAS (including KRAS, NRAS and HRAS) or BRAF mutations were associated with late distant metastases and the prognosis of patients with colorectal cancer (CRC). A total of 374 patients with stage III CRC were classified into 4 groups based on RAS/BRAF and C-MET status for comprehensive analysis. Mutations in RAS/BRAF were determined using Sanger sequencing and C-MET expression was examined using immunohistochemistry. The associations between RAS/BRAF mutations in combination with C-MET overexpression and clinicopathological variables including survival were evaluated. In addition, their predictive value for late distant metastases were statistically analyzed via logistic regression and receiver operating characteristic analysis. Among 374 patients, mutations in KRAS, NRAS, HRAS, BRAF and C-MET overexpression were observed in 43.9, 2.4, 0.3, 5.9 and 71.9% of cases, respectively. Considering RAS/BRAF mutations and C-MET overexpression, vascular invasion (P=0.001), high carcino-embryonic antigen level (P=0.031) and late distant metastases (P<0.001) were more likely to occur in patients of group 4. Furthermore, survival analyses revealed RAS/BRAF mutations may have a more powerful impact on survival than C-MET overexpression, although they were both predictive factors for adverse prognosis. Further logistic regression suggested that RAS/BRAF mutations and C-MET overexpression may predict late distant metastases. In conclusion, RAS/BRAF mutations and C-MET overexpression may serve as predictive indicators for metastatic behavior and poor prognosis of CRC.

Keywords: RAS; c-mesenchymal epithelial transition factor; colorectal cancer; metastasis; prognosis.

Figure 1.

Mutation subtypes frequency distribution of (A) KRAS and (B) NRAS.

Figure 2.

Analysis of C-MET expression by immunohistochemistry in colorectal carcinomas. C-MET expression was localized in the membrane and its expression was observed predominantly in cancer cells. (A) Negative C-MET staining in a cancerous tissue sample (magnification, ×100). (B) Positive C-MET staining in tumor cells (upper), with negative or weak staining in adjacent epithelial cells (lower) (magnification, ×100). (C) Strong C-MET staining in tumor nests (magnification, ×100). (D) Positive membrane staining, as observed in the majority of tumor cells (magnification, ×200). C-MET, c-mesenchymal epithelial transition factor.

Figure 3.

Kaplan-Meier survival curves of patients with stage III colorectal carcinoma. (A) OS and (B) DFS in all wild-type vs. RAS/BRAF mutations. (C) OS and (D) DFS in low C-MET expression vs. C-MET overexpression of entire study population. OS, overall survival; DFS, disease-free survival; C-MET, c-mesenchymal epithelial transition factor; CI, confidence interval.

Figure 4.

Kaplan-Meier survival curves of patients with colorectal carcinoma classified according to RAS/BRAF mutations and C-MET status. (A) OS and (B) DFS based on the combinational status of RAS/BRAF and C-MET. OS, overall survival; DFS, disease-free survival; C-MET, c-mesenchymal epithelial transition factor.

Figure 5.

ROC curves for the predictive ability of RAS/BRAF mutations and C-MET overexpression to late distant metastasis. ROC, receiver operating characteristic curve; C-MET, c-mesenchymal epithelial transition factor.