Intrinsic Genomic Differences Between African American and White Patients With Clear Cell Renal Cell Carcinoma

Abstract

Importance There are well-documented racial disparities in outcomes for African American patients with clear cell renal cell carcinoma (ccRCC). Despite a dramatic improvement in overall survival in white patients since the advent of targeted therapy, survival for African Americans with advanced ccRCC has not changed. There is little known about potential racial differences in tumor biology of ccRCC. Objective To determine if there are racial differences in the somatic mutation rate and gene expression of ccRCC tumors from white and African American patients. Design, Setting, and Participants Overall, 438 patients with ccRCC were identified through The Cancer Genome Atlas (TCGA) clear cell kidney (KIRC) dataset (419 white and 19 African American patients). The GSE25540 dataset containing 135 patients (125 white and 10 African American patients) was used for validation. Tumor samples were collected from numerous cancer centers and were examined for racial differences in somatic mutation rates and RNA expression. Racial differences in somatic mutation rates and RNA expression were examined. Main outcomes and Measures The comparison of somatic mutation rates and differences in RNA expression in white and African American patients with ccRCC. Results Overall, 419 ccRCC tumor data sets from non-Hispanic white patients and 19 from non-Hispanic African American patients were identified through the publically available TCGA KIRC data set, and a validation set of 125 white and 10 African American ccRCC patient tumors was identified from the publicly available GSE25540 data set. African American patients were significantly less likely than white patients to have VHL mutations (2 of 12 [17%] vs 175 of 351 [50%], respectively; P = 04) and were enriched in the ccB molecular subtype (79% in African American vs 45% in white patients; P = 005), a molecular subtype that carries a worse prognosis. It was found that RNA expression analysis revealed relative down-regulation of hypoxia-inducible factor (HIF) and vascular endothelial growth factor (VEGF)-associated pathways in African American patients compared with white patients. Conclusions and Relevance African American patients have less frequent VHL inactivation, are enriched in the ccB molecular subtype, and have decreased up-regulation of HIF-associated gene signatures than white patients. These genomic differences would predict decreased responsiveness to VEGF-targeted therapy and are a biologically plausible contributing factor to the worse survival of African American patients with ccRCC, even in the targeted therapy era.

Racial disparities in pancreatic neuroendocrine tumors survival: a SEER study

“…Also, for multiple myeloma, African American's higher levels of phenotypic heterogeneity and monoclonal immunoglobulin levels caused the unfavorable survival, compared with their white counterparts . Compared with Whites, African Americans have also been proved to have worse survival in other tumors due to racial genetic differences, including head and neck squamous cell carcinoma, kidney cancer . However, no study has specifically explored pancreatic NETs‐related genetic differences in races and ethnicities and their contribution to pancreatic NETs survival disparity.…”

Racial disparities in survival among patients with advanced renal cell carcinoma in the targeted therapy era

“…2 On the basis of data from The Cancer Genome Atlas, our group recently demonstrated that tumors from AA patients who have clear cell RCC are less likely to harbor von Hippel-Lindau (VHL) mutations, have lower RNA expression of hypoxia-inducible factor and VEGFassociated pathways, and are more likely to have the more aggressive clear cell B subtype. 19 These differences suggest that AAs with clear cell RCC may be less likely to respond to VEGF-targeted therapy and that differences in tumor biology may drive some of the observed survival disparity. Our current study supports the potential role of tumor biology in the racial disparity in survival, because, after adjustment for clinical factors, the survival disparity persists between races.…”

Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers

“…This shared genetic background may confer similarities in cancer incidence and outcomes in populations. Recent large-scale genomic profile studies in individual cancer types, such as prostate (Huang et al, 2017; Petrovics et al, 2015; Powell et al, 2013; Wang et al, 2017), breast (Ademuyiwa et al, 2017; Huo et al, 2017; Keenan et al, 2015; Loo et al, 2011), colon (Guda et al, 2015), lung (Araujo et al, 2015; Campbell et al, 2017; Kytola et al, 2017), gastric (Schumacher et al, 2017), esophageal (Deng et al, 2017), and kidney (Krishnan et al, 2016) cancers have robustly demonstrated that genomic differences in cancers exist among distinct racial and ethnic populations. Consistently, it has been reported that the genetic background of patients may influence specific somatic alterations in cancer genomes during tumorigenesis (Carter et al, 2017).…”