Molecular stratification and characterization of clear cell renal cell carcinoma Public Deposited

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  • March 22, 2019
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  • Brannon, Angela R.
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • It is estimated that there will be 58,240 new diagnoses of kidney cancer in 2010. Most cases will be clear cell renal cell carcinoma (ccRCC) and have little information as to how their disease will progress. This diversity of disease natural history is especially noteworthy in a disease so well characterized by the inactivation of the von Hippel Lindau (VHL) tumor suppressor and resulting stabilization of Hypoxia Inducible Factors (HIF). Previous studies had suggested the presence of two or more clusters in ccRCC. Based on the nonuniformity within the disease's natural progression and previous research, we hypothesized that distinct inherent molecular subclasses of ccRCC must exist and, therefore, sought to define and characterize them. In fact, two robust subtypes of ccRCC were identified, designated ccA and ccB. These subtypes are associated with survival by multivariate analysis, conferring a median survival of 8.6 years versus 2 years, respectively. We postulated that the underlying molecular pathways within the data would explain the survival difference. ccA tumors overexpress angiogenesis, hypoxia, and metabolism pathways, common pathways characterizing ccRCC tumors. In contrast, ccB tumors overexpress more aggressive genes related to epithelial to mesenchymal transition, cell cycle, and Wnt targets. VHL analysis and HIF immunohistochemistry suggests that neither appear to be driving subtype differences. To understand what is causing the differences, underlying genetic changes were analyzed. Both subtypes show deletion of chromosome 3p, location of VHL, in greater than 75% of tumors, corresponding with previous research and suggesting a common initiating tumorigenic event. Overall, copy number patterns look very similar between the subtypes; however, more ccB tumors show deletion of chromosomes 9 and 14, which previous studies have shown to correlate with decreased survival. Additionally, ccA tumors have mutations in a number of histone modification genes, suggesting that epigenetic modification may play a role in subtype differences. Finally, a biomarker panel of 120 probes was defined to distinguish ccA and ccB tumors. This panel is the basis of an assay using FFPE tissue for clinical use. This assay will classify tumors into the inherent subtypes identified by this study, with prognostic impact and potentially predictive import.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Genetics and Molecular Biology."
Advisor
  • Rathmell, W. Kimryn
Degree
  • Doctor of Philosophy
Graduation year
  • 2010
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