Genomics of Renal Cancer in Patients of African Ancestry

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PROJECT SUMMARY The outcomes of Black patients are worse than white patients across renal cell carcinoma (RCC) subtypes. Black patients also suffer higher disease incidence compared to the white patient population, particularly for the papillary subtype. Environmental and structural factors likely contribute to this disparity; however, there is evidence suggesting that somatic genomic differences also contribute. Although patients of African (AFR) ancestry are under-represented in most publicly available databases, decreased VHL gene mutation and chromosome 3p deletion in clear cell RCC patients of AFR ancestry was observed compared to European (EUR) ancestry. In our preliminary data with increased sample size, we found NF2 mutations and chromosome 22q deletion to be more frequent in RCCs from patients of AFR ancestry across subtypes. These preliminary findings of genomic correlations with ancestry lead us to hypothesize that the survival disparity may be partially explained by molecular features enriched in tumors from patients of AFR ancestry. In this project, we will take three parallel approaches to understanding the molecular tumor differences between patients of AFR and EUR ancestry. In the first aim, we will perform a comprehensive computational analysis of larger RCC datasets to validate and identify new genomic tumor differences between these two patient populations. In the second aim, we will functionally characterize the “ancestry-specific” genomic alterations identified in preliminary studies, including two aneuploidy events - chromosome 3p deletion and chromosome 22q deletion. Lastly, in the third aim, we will move beyond panel and exome sequencing to identify new driver events, using whole-genome sequencing coupled with RNA-sequencing on tumors from Black patients. The results from these experiments will lead to new insights about the specific biology of RCC in this patient population. Our studies will reveal ancestry-associated driver alterations that could not only improve diagnostic testing for RCC patients of AFR ancestry, but will also identify new therapeutic targets to decrease the disparities observed in RCC.