Background Over 40% of renal cell carcinoma (RCC) cases in the US are attributed to excessive body weight. Moreover, obesity may also be linked to RCC prognosis. However, the molecular mechanism underlying these associations are unclear. In the present study, we evaluated the role of promoter methylation in obesity-related genes in RCC tumorigenesis and recurrence. Methods Paired tumors (TU) and normal adjacent (N-Adj) tissues of 240 newly diagnosed and previously untreated Caucasian RCC patients were examined. For the discovery phase, 63 RCC-pairs were analyzed. Additional 177 RCC-pairs were evaluated for validation. Pyrosequencing was used to determine CpG methylation in 20 candidate obesity-related genes. An independent TCGA dataset was also analyzed for functional validation. Association between methylation and recurrence was analyzed using multivariate Cox proportional hazards models and Kaplan-Meier survival analysis. Results Methylation in NPY, LEP and LEPR was significantly higher in TU compared with N-Adj tissues (p<0.0001) in both discovery and validation groups. High methylation in LEPR was associated with increased risk of recurrence (HR=3.15; 95%CI: 1.23–8.07; p=0.02). Patients with high-methylation in LEPR had shorter recurrence-free survival than low-methylation group (Log-Rank p=2.25E-03). Additionally, high LEPR methylation in TU was associated with more advanced features (p≤0.05). Consistent with our findings, lower LEPR expression in TU compared with N-Adj tissues (p=1.00E-03) was found in TCGA data. Conclusions Somatic alterations of promoter methylation in NPY, LEP and LEPR genes are involved in RCC-tumorigenesis. Furthermore, LEPR methylation is associated with RCC recurrence. Future research to elucidate the biology underlying this association is warranted.

Purpose 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 renal cell carcinoma (RCC). Experimental Design A retrospective case control study consisting of 889 RCC cases and an equal number of age, gender, and ethnicity-matched controls was applied. Global DNA methylation was measured as 5-mC% content. 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. Results The median 5-mC% was significantly lower in cases than healthy controls (p<0.001). In multivariate logistic regression analysis, individuals in the lowest tertile (T1) of 5-mC% had higher risk of RCC with OR of 1.40 (95%CI 1.06–1.84), compared to individuals in the highest tertile (T3) (Pfor trend=0.02). When stratified by RCC risk factors, associations between hypomethylation and increased RCC risk appeared to be stronger among males (OR=1.61, Pfor trend=0.01), younger age (OR=1.47, Pfor trend=0.03), never smokers (OR=1.55, Pfor trend=0.02), family history of other cancer (OR=1.64, Pfor trend=1.22E-03) and late stage (OR=2.06, Pfor trend=4.98E-04). Additionally, we observed significant interaction between gender and 5-mC% in elevating RCC risk (Pfor interaction=0.03). Conclusions Our findings suggest an association between global DNA hypomethylation and RCC risk. To establish global DNA hypomethylation as a risk factor for RCC, future prospective studies are warranted. This study may provide further understanding of the etiology of RCC tumorigenesis.

Despite having a favorable response to platinum-based chemotherapies, ~15% of Testicular Germ-Cell Tumor (TGCT) patients are platinum-resistant. Mortality rates among Latin American countries have remained constant over time, which makes the study of this population of particular interest. To gain insight into this phenomenon, we conducted whole-exome sequencing, microarray-based comparative genomic hybridization, and copy number analysis of 32 tumors from a Mexican cohort, of which 18 were platinum-sensitive and 14 were platinum-resistant. We incorporated analyses of mutational burden, driver mutations, and SNV and CNV signatures. DNA breakpoints in genes were also investigated and might represent an interesting research opportunity. We observed that sensitivity to chemotherapy does not seem to be explained by any of the mutations detected. Instead, we uncovered CNVs, particularly amplifications on segment 2q11.1 as a novel variant with chemosensitivity biomarker potential. Our data shed light into understanding platinum resistance in a Latin-origin population.