Role of LINE-1 Methylation Status of Adjacent Normal Colonic Mucus in the Survival of Chinese Patients with Colon Cancer.

e14514 Background: As a global epigenetic change, LINE-1 hypomethylation in normal mucosa were reported to have a key role in forming a ‘field defect’ in colorectal carcinogenesis. We aimed to study its influence on the survival of Chinese colon cancer patients. Methods: Tissue samples of tumor or normal mucosa were utilized to detect certain genetic and epigenetic modifications. Prognostic variables for the patients’ survivals were determined and the influence of LINE-1 methylation rate (LMR) level was further analyzed by survival studies. Results: Overall, 127 patients, 83 males and 44 females, completed a median follow-up of 65 (3-85) months. It was revealed 14 (11.02%) and 5 (3.94%) cases mutated in KRAS and BRAF gene, respectively. Sixteen (12.60%) were confirmed as MSI-H, and 76 (59.84%) were found to have a loss of heterozygosity (LOH) at 18q. There were 26 (20.47%) cases defined as hypermethylation at hMLH1 gene promoter. A mean of 64.42 (9.45-86.93) % of LMRs were determined by pyrosequencing and further sub-grouped into high or low level by X-tile program. Cox multivariate analysis confirmed that the LMR level (high vs. low, HR = 0.396, 95% CI: 0.194-0.805, p = 0.011), MSI status (MSI-H vs. MSS or MSI-L, HR = 0.082, 95% CI: 0.011-0.629, p = 0.016), and distant metastases (M1 vs. M0, HR = 28.006, 95% CI: 11.380-68.920, p = 0.000) were the independent prognostic factors for colon cancer specific survival. Sub-layer analysis revealed that patient with lower LMR level had a significantly worse survival in the subgroups of M0, right-sized colon, size ≤ 5 cm, Stage I-III, MSI-L or MSS, serum CEA at normal level, age > 60 years, 18q LOH, BRAF gene wild-types, KRAS gene mutation, etc. (all with p < 0.05). Conclusions: Genetic and epigenetic alterations can concurrently exist in the complex mechanisms of colonic tumorigenicity. Hypomethylation of LINE-1 at adjacent normal mucosa might be associated with worse outcome in certain Chinese patients with colon cancer. Acknowledgements: This work was supported by the National Natural Science Foundation of China (No. 81372646 to Cai SJ, No. 81472222 to Li DW, and No. 51377024 to Li XX).