Fellow Johns Hopkins University Baltimore, MD, United States
Background: Clinical studies evaluating the impact of race on outcomes in renal cell carcinoma (RCC) are inconsistent and conceivably influenced by both biological and socioeconomic factors. Self-reported African Americans (AA) are also largely underrepresented in clinical trials and molecular studies of clear cell (cc)RCC compared to their White (W) counterparts. Herein, we sought to comprehensively characterize molecular differences by genetic ancestry in ccRCC.
Methods: We performed whole exome (WES) and transcriptome (RNAseq) sequencing on a case-matched cohort of AA and W patients who underwent nephrectomy for ccRCC at our institution. Genetic ancestry was estimated using the 1000 Genomes Project for reference. Molecular subtypes were defined according to the IMmotion151 (IMm151) subtypes.
Results: From an initial cohort of 67 pts, WES and RNAseq data of adequate quality were available for 57 patients including 27 of African (AFR) and 30 of European (EUR) descent. We augmented our institutional cohort with a 3:1 EUR:AFR propensity-matched subset of the TCGA. The final cohort contained 74 patients of AFR and 171 patients of EUR descent. There were no differences in baseline clinical variables between groups. AFR ancestry was associated with an increased proportion of the proliferative IMm151 subtype (19.7% [n = 14/71] vs 1.8% [n = 3/168], p < 0.00001). There were significant differences in the frequency of VHL (AFR: 26.2% EUR: 59.0%, p< 0.001) and KMT2C (AFR: 12.3% vs EUR: 3.0%, p = 0.01) alterations between ancestry groups. However, after adjusting for the IMm151 subtype, genetic ancestry failed to account for additional variance in gene expression or somatic alterations. Concordant with this, IMm151 subtypes, but not genetic ancestry, stratified overall survival (p < 0.001).
Conclusions: Our findings indicate a significant association between genetic ancestry and molecular subtypes of ccRCC, underscoring the need for racially diverse representation in future studies.
