Somatic expression of ENRAGE is associated with obesity status among patients with clear cell renal cell carcinoma

An association between obesity and development of clear cell renal cell carcinoma (ccRCC) has been established in the literature; however, there are limited data regarding the molecular mechanisms that underlie this association. Therefore, we used a multistage design to identify and validate genes that are associated with obesity-related ccRCC. We conducted a microarray study and compared gene expression between obese and non-obese subjects in ccRCC tumors and patient-matched normal kidney tissues. Analyses were stratified by smoking status and subsequently performed on the combined cohort. The primary objective was to identify genes where the fold change of ccRCC tumor expression between obese and non-obese subjects was different than the fold change in the patient-matched normal kidney tissue. Thus, we utilized a mixed model and evaluated the tissue type-by-obesity status interaction term. Targeted validation was performed using reverse transcription-polymerase chain reaction (RT-PCR) on an independent cohort. ENRAGE was identified in the microarray study and subsequently validated using RT-PCR to have a statistically significant tissue type-by-obesity status interaction. Specifically, although ENRAGE is similarly expressed across obese and non-obese subjects in normal tissue, it is upregulated in the patient-matched ccRCC tumor tissue. Additionally, ENRAGE is upregulated in tumors that are wild-type for the von Hippel Lindau gene and in tumors for subjects with poorer overall survival. In summary, we provide evidence that overexpression of ENRAGE in ccRCC tumor tissue is an obesity-associated somatic alteration. Upregulation of ENRAGE could lead to local, autocrine stimulation of the RAGE receptor and thus support cancer progression.