Changhua Zhuo¹, Qingguo Li¹, Xinxiang Li¹, Sanjun Cai²

¹Department of surgical Oncology, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, ²Department of Colorectal Surgery, Fudan University Shanghai Cancer Center

Objective:Genetic and epigenetic pathways are not independent in colorectal cancer (CRC) carcinogenesis. We aimed to determine the influence of various molecular features on Chinese patients' colon cancer-specific survival (CCSS). Method: Various genetic and epigenetic modifications were detected in paired tumor and normal mucosa tissue samples. The prognostic variables regarding patient CCSS were determined. Result: Overall, 127 patients, including 83 males and 44 females, completed a median follow-up of 65 (3-85) months. A mean LINE-1 methylation rate (LMR) of 64.62% (range, 9.45-86.93) was observed. Hypermethylation at the hMLH1 gene promoter was detected in 26 (20.47%) patients. KRAS was mutated in 52 (40.94%) patients. Sixteen (12.60%) patients were confirmed as microsatellite instability (MSI)-High, and 76 (59.84%) were found to have loss of heterozygosity (LOH) at chromatin chromosome 18q. The multivariate Cox regression analysis confirmed that the LMR (high vs. low, hazard ratio (HR)=0.337, 95% confidence interval (CI): 0.162-0.702, P=0.004), MSI status (MSI-High vs. MSI-Low/microsatellite stable (MSS), HR=0.088, 95% CI: 0.011-0.679, P=0.020), perineural invasion (yes vs. no, HR=2.578, 95% CI: 1.148- 5.791, P=0.022), and distant metastases (M1 vs. M0, HR=28.641, 95% CI: 11.414-71.870, P=0.000) were independent prognostic factors of CCSS. A stratified survival analysis further revealed that patients with a lower LMR had a significantly worse survival in the subgroups of age>60 years, tumor size ≤5 cm, right-sided tumors, M0, differentiation grade of G3-G4, no perineural invasion, normal serum CEA levels, KRAS gene mutation, wild-type BRAF and PIK3CA, 18q LOH, and no hMLH1 gene promoter hypermethylation (all P<0.05). Conclusion: Our data revealed that both genetic and epigenetic abnormalities can concurrently exist during colonic tumorigenesis. As a global epigenetic change, LINE-1 hypomethylation in normal colon mucosa might be associated with a worse outcome in certain Chinese patients with colon cancer.

Key Words: Epigenetic modification  LINE-1  microsatellite