Abstract 2634: Prognostic value of obesity-related genes methylation in localized renal cell carcinoma patients
Authors: Mendoza-Perez Julia , Gu Jian , Tannir Nizar M. , Matin Surena , Karam Jose A. , Huang Maosheng , Xiang Shu , Chang David W. , Wood Christopher G. , Herrera Luis A. , Wu Xifeng 
Published: July 2016

Abstract
Obesity is an established risk factor for renal cell carcinoma (RCC): more than 40% of RCC cases in US are attributed to excessive body weight. Growing evidence suggests that obesity may also be associated with the prognosis of RCC. The molecular mechanism linking obesity and RCC is not well understood. In the present study, we evaluated the association between promoter CpG island methylation of 20 obesity-related genes and RCC. A total of 275 newly diagnosed and previously untreated Caucasian RCC patients were included. For the discovery population, 75 tissue pairs of RCC tumors and normal adjacent tissues from the surrounding kidney were used and for the validation population an additional 200 pairs were included. Pyrosequencing was used to determine CpG site methylation on bisulfite-treated genomic DNA. We used Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confident intervals (CIs) for the association of CpG methylation with recurrence and Kaplan-Meier curve to plot disease free survival (DFS) time by different CpG site methylation. The average age of the patients was 59 years and they were largely males; ∼50% were never smokers. Most of the cases were clear cell RCC (ccRCC) and clinical stage I. Among the 20 markers, LEP, LEPR and NPY were significantly hypermethylated in tumor tissues compared to normal tissues (p&lt;0.0001) in the discovery set. Similar results were obtained in the validation set. Moreover, LEPR methylation in tumors was associated with recurrence. When patients were dichotomized into high and low methylation groups according to the median value of LEPR methylation, high LEPR methylation was associated with a significantly higher risk of recurrence (HR = 2.4, 95% CI, 1.03-5.8), adjusted by age, gender, clinical stage, grade, smoking status, BMI, hypertension and histology. The Kaplan-Meier analysis showed a shorter 5-year DFS probability for the patients with high LEPR methylation level (34.7%) compared with low methylation (41.7%) (LogRank, p = 0.032). The MST was 39 months in high methylation group and 47 months in low methylation. Our results suggest that LEPR hypermethylation in tumors is associated with recurrence in RCC patients and thus LEPR may provide a functional link between obesity and RCC. Future studies are needed to elucidate the biology underlying the association of LEPR methylation and RCC recurrence. 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 MD Anderson Cancer Center.
Citation Format: Julia Mendoza-Perez, Jian Gu, Nizar M. Tannir, Surena Matin, Jose A. Karam, Maosheng Huang, Shu Xiang, David W. Chang, Christopher G. Wood, Luis A. Herrera, Xifeng Wu. Prognostic value of obesity-related genes methylation in localized renal cell carcinoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2634.