AbstractBackgroundThe United States is becoming increasingly diverse, but few molecular studies have assessed the progression of clear cell renal cell carcinoma (ccRCC) in diverse patient populations. This study examined ccRCC molecular variations in non‐Hispanic White (NHW) and Hispanic patients and their effect on the association of gene expression with high‐grade (Grade 3 or 4) ccRCC and overall mortality.MethodsA total of 156 patients were included inVHLsequencing and/or TempO‐Seq analysis. DESeq2 was used to identify the genes associated with high‐grade ccRCC. Logistic regression analysis was performed to assess whether race and ethnicity was associated with high/moderate impactVHLsomatic mutations and the ccA/ccB subtype. Cox regression analysis was performed to assess association of molecular subtype and gene expression with overall mortality.ResultsNHWs had moderate or high impact mutations in theVHLgene at a higher frequency than Hispanics (40.2% vs. 27.4%), while Hispanics had a higher frequency of the ccA subtype than NHWs (61.9% vs. 45.8%). ccA was more common in patients with BMI≥35 (65.2%) than in those with BMI < 25 (45.0%). There were 11 differentially expressed genes between high‐ and low‐grade tumors. TheHaptoglobin(HP) gene was most significantly overexpressed in high‐ compared to low‐grade ccRCC in all samples (p‐adj = 1.7 × 10−12). When stratified by subtype, the 11 genes were significantly differentially expressed in the ccB subtype, but none of them were significant after adjusting for multiple testing in ccA. Finally, patients with the ccB subtype had a significantly increased risk of overall mortality (HR 4.87;p= 0.01) compared to patients with ccA, and patients with highHPexpression and ccB, had a significantly increased risk of mortality compared to those with lowHPexpression and ccA (HR 6.45,p= 0.04).ConclusionThis study reports ccRCC molecular variations in Hispanic patients who were previously underrepresented.