Abstract 159: LINE-1 hypomethylation and patient prognosis in 1118 colorectal cancers

Abstract

Abstract Background: Global DNA hypomethylation plays an important role in activation of oncogenes in a genome-wide scale, chromosomal instability and colorectal carcinogenesis. DNA methylation in LINE-1 (L1) repetitive element has been correlated with global DNA methylation level. We examined LINE-1 methylation in colorectal cancer and patient survival. Methods: Utilizing 1118 colorectal cancers in two prospective cohorts, we quantified methylation in a LINE-1 by Pyrosequencing. Kaplan-Meier method and Cox proportional hazard models were used to assess differences in colon cancer-specific and overall mortalities in univariate analysis and multivariate analysis that adjusted for patient characteristics and tumoral molecular features, including BRAF mutation, the CpG island methylator phenotype and microsatellite instability. Results: LINE-1 hypomethylation in 875 colon cancers was independently and linearly associated with high colon-cancer specific mortality (Ptrend<0.0001) and overall mortality (Ptrend=0.0004). Compared to patients with ≥75% LINE-1 methylated tumors, the adjusted hazard ratio (HR) for colon cancer-specific mortality were 1.36 [95% confidence interval (CI), 0.76-2.41] for 60-75% LINE-1 methylated tumors, 1.98 (95% CI, 1.10-3.55) for 45-60% LINE-1 methylated tumors, and 3.83 (95% CI, 1.87-7.84) for <45% LINE-1 methylated tumors. Similar findings were noted for overall mortality. Kaplan-Meier analysis demonstrated shorter survival among patients with LINE-1 hypomethylated tumors (log-rank p<0.0001). The prognostic influence of LINE-1 hypomethylation in colon cancer was consistent across the two independent cohort studies as well as across strata of clinical or molecular characteristics. In contrast, LINE-1 hypomethylation was not significantly associated with survival of 243 rectal cancer patients (adjust HR 1.02; 95% CI, 0.48-2.19; for a 30% decrease of LINE-1 methylation; Ptrend=0.96). Conclusions: Tumoral LINE-1 hypomethylation is associated with shorter survival among colon cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 159.