Abstract 51: Prospective study of LINE-1 hypomethylation in peripheral leukocyte DNA and colorectal cancer risk.

Abstract

Abstract Background: The family of long interspersed nuclear elements (LINE-1) retrotransposons is reportedly hypomethylated in many cancers and reflects global methylation status in the genome. Global hypomethylation in peripheral blood leukocyte DNA has been increasingly studied and associated with increased risk of cancer, including colorectal cancer and adenoma in cross-sectional studies. Methods: To minimize disease- and/or treatment-related effects, we studied LINE-1 methylation levels in prospectively collected blood specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in relation to subsequent colorectal cancer risk. In a nested study of 398 cases and 519 controls who were cancer-free at blood collection, the extent of LINE-1 hypomethylation was measured by using the McrBC methylation specific restriction enzyme to cut methylated but not unmethylated DNA, followed by real-time PCR of the undigested/unmethylated LINE1 promoter sequences. We estimated the association between colorectal cancer risk and LINE-1 methylation categories by computing odds ratios (ORs) and 95% confidence intervals (CIs) through multivariable logistic regression modeling. Results: Overall, we observed no clear association between colorectal cancer and LINE-1 methylation categories (lowest tertile vs. highest: OR=1.06, 95% CI=0.74-1.52; P trend=0.72). However, we observed a nearly significant trend of decreasing LINE-1 methylation (hypomethylation) associated with increasing colorectal cancer risk, after excluding cases diagnosed within 1 year (lowest tertile vs. highest: OR=1.40, 95% CI=0.87-2.27; P trend=0.14) and 5 years (OR=2.65, 95% CI=0.96-7.36; P trend=0.07) following the blood collection. We noted no significant risk modification by folate intake or other suspected risk factors of colorectal cancer, such as smoking, obesity, and aspirin/ ibuprofen use in analyses including all subjects or excluding cases diagnosed within 5 years following blood collection (P interaction ranged between = 0.12 to 0.98). Conclusion: Findings from this prospective investigation offer further support for a potential dose-dependent relationship between LINE-1 hypomethylation in leukocyte DNA and subsequent colorectal cancer risk. Citation Format: Wen-Yi Huang, L. Joseph Su, Sonja I. Berndt, Lee E. Moore, Hormuzd A. Katki, Srinivasan Yegnasubramanian, Mark P. Purdue. Prospective study of LINE-1 hypomethylation in peripheral leukocyte DNA and colorectal cancer risk. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 51.