LINE-1 hypomethylation in normal colon mucosa is associated with poor survival i
PUBLISHED: 2015-11-27  431 total views, 1 today

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

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