Intrinsic Genomic Differences Between African American and White Patients With Clear Cell Renal Cell Carcinoma
Open accessAbstract
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.
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VHL gene mutations lead to stability of HIF subunits and constitutive activation of HIF-mediated transcriptional pathways in patients with VHL, causing progression of renal cell carcinoma.
“VHL gene mutations lead to the stability of HIF subunits and the constitutive activation of HIF‐mediated transcriptional pathways in patients with VHL, causing the progression of renal cell carcinoma.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [26]
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García-Cárdenas, J. M., Morán-Erazo, C., Chávez-Vélez, E., Terán-Navas, M., Aleaga, A., Armendáriz‐Castillo, I., López‐Cortés, A., Pesántez, D., Indacochea, A., & Guerrero, S. X. (2024) · Interdisciplinary cancer research · doi:10.1007/16833_2024_257
Suliman, R., & Alfaki, M. (2025) · Cureus · doi:10.7759/cureus.99926
- Authors
- Krishnan, B., Rose, T. L., Kardos, J., Milowsky, M. I., & Kim, W. Y.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Kim, William Y.
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2016-05-01
- Volume
- 2
- Issue
- 5
- Pages
- 664
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC5035632
- OpenAlex
- W2311389132
- Cited by
- 75
- References
- 17
- Citations by year
- 2025: 9 · 2024: 7 · 2023: 7 · 2022: 5 · 2021: 11 · 2020: 20 · 2019: 6 · 2018: 4 · 2017: 4 · 2016: 2
- FWCI
- 4.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Oncology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2k12ca120780-16)
- National Cancer Institute (K12-CA120780, R43CA120297, P30CA016086)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- clear cell renal cell carcinoma, racial disparities, African American patients, somatic mutations, VHL mutation, hypoxia-inducible factor pathway, VEGF pathway, gene expression, tumor biology, targeted therapy response, prognostic subtypes, overall survival
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