Abstract 2953: Genomic DNA hypomethylation as an independent risk factor for renal cell carcinoma

Abstract

Abstract Renal cell carcinoma (RCC) is the most lethal genitourinary cancer. Cigarette smoking, hypertension and obesity are the major risk factors for RCC; however, much of the etiology of this disease remains to be elucidated. Genomic DNA hypomethylation is a hallmark of most cancer genomes, promoting genomic instability and cell transformation. In the present study, we sought to determine whether global DNA methylation in peripheral blood is associated with risk of RCC. A case control study consisting of 889 RCC cases and an equal number of age, gender, and ethnicity-matched controls was conducted. Genomic DNA was isolated from peripheral blood and global DNA methylation was measured as 5-mC% content using an antibody-based immune assay. Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between DNA methylation level and the risk of RCC. The median age was 59.29±10.42 for cases and 59.39±10.30 for controls. Over two-thirds (67% in both cases and controls) were males, about half (50.2% in cases and 52.2% in controls) were never smokers, the vast majority (84.8% in both cases and controls) were Caucasian. BMI, physical activity, hypertension and family history of cancer were significantly different between cases and controls. RCC cases are more likely than controls to have high blood pressure level (p = 5.81E-15), higher BMI (p = 0.011), low physical activity (p = 1.48E-20), and a family history of cancer (other than kidney cancer) (p = 5.42E-07). The median methylation level in controls was 3.97, significantly higher than the median level of 3.64 in cases (p<0.001 Wilcoxon rank-sum test). In multivariate logistic regression analysis adjusted by age, gender, ethnicity, smoking status, and hypertension, individuals in the lowest tertile (T1) and middle tertile (T2) of 5-mC% had higher risks of RCC with ORs of 1.42 (95%CI 1.12-1.81) and 1.14 (95% CI 0.89-1.45), respectively, compared to individuals in the highest tertile (T3) of methylation (p for trend 0.004). When stratified by RCC risk factors, associations between hypomethylation and increased RCC risks were stronger among males (OR 1.64, 95%CI 1.21-2.21), younger individuals (OR 1.54, 95%CI 1.10-2.15), never-smokers (OR 1.61, 95%CI 1.14-2.28) and African-Americans (OR 2.75, 95%CI 0.75-10.08). These findings suggest for the first time that global DNA hypomethylation in peripheral blood is independently associated with RCC risk. The results may provide better understanding of the etiology of RCC tumorigenesis and in combination with modifiable risk factors and other potential biomarkers, may help identify high risk individuals for screening and early detection of RCC. This work was supported in part by the National Institutes of Health (grant R01 CA170298) and the Center for Translational and Public Health Genomics, Duncan Family Institute for Cancer Prevention, The University of Texas M D Anderson Cancer Center. Citation Format: Julia Mendoza Perez, Jian Gu, Nizar M. Tannir, Surena Matin, Jose A. Karam, David W. Chang, Luis A. Herrera, Christopher G. Wood, Xifeng Wu. Genomic DNA hypomethylation as an independent risk factor for renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2953. doi:10.1158/1538-7445.AM2015-2953