Despite development of new technologies, a challenge in the diagnosis of renal cell carcinoma (RCC) is the accurate assessment of tumor aggressiveness. Currently, tumor size is the main criteria used to assess the stage of the tumor per the American Joint Committee on Cancer (AJCC) 2010. Considering that RCC tumors are heterogeneous, techniques looking beyond tumor size are highly warranted. Highly aggressive tumors may be small at presentation and recognition of these has implications in changing management and follow up. The parallel advances in deciphering of the molecular biology underpinnings of RCC and development of new epigenomics biomarkers have provided new opportunities to more accurately assess tumor aggressiveness and aid in a more accurate tumor staging. Therefore, we identify an unmet clinical need i.e., the lack of reliable noninvasive biomarkers for pre-operative differentiation of renal masses based on their aggressiveness. This can lead to removal of indolent lesions resulting in unnecessary surgery, morbidity, and costs. As a solution, we propose to use radiomics (high-throughput feature extraction) data extracted from standard-of-care imaging (here contrast enhanced computed tomography (CECT)) to derive diagnostic and prognostic biomarkers of tumor aggressiveness (specific aim 1). Further, indeterminate lesions identified by the radiomics method can then be targeted by biopsies and genomic features such as DNA methylation markers to further improve the specificity of the prediction (specific aim 2). We expect that this RADIOEPIGENOMICS approach, developed, optimized and piloted as a part of this project, will improve diagnostic accuracy, and optimize criteria used for assessing tumor aggressiveness. At the completion of this project, we will have pilot data to commence a larger study with RCC patients that will have a high impact on patient care by providing new objective imaging-based means for deciphering tumor aggressiveness and use to tailor various treatments in a “personalized” patient-specific manner. This team is resubmitting (Nov 2016) NIH R01 grant looking (Impact Score of 37, Percentile-25 from initial submission) at utility of a novel radioepigenomics platform for differentiating benign from malignant renal masses. This proposed pilot project will allow us to collect additional data looking at the utility of this platform for differentiating aggressive from indolent tumors which will then be submitted as another NIH R01 grant in Fall 2017.