M Nientiedt1, K Müller2, K Nitschke2, P Erben2, A Steidler2, S Porubsky3, Z V Popovic4, F Waldbillig2, J Mühlbauer2, M C Kriegmair2. 1. Department of Urology and Urosurgery, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. malin.nientiedt@umm.de. 2. Department of Urology and Urosurgery, Medical Faculty Mannheim, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany. 3. Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 4. Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
Abstract
PURPOSE: To investigate the mRNA expression of B-MYB and MDM2 together with their p53 relatedness in clear cell renal cell carcinoma (ccRCC). METHODS: Genes were screened for their mRNA expression from 529 patients in a publicly available ccRCC cohort (TCGA). A cohort of 101 patients with ccRCC served as validation by qRT-PCR mRNA tissue expression analysis. RESULTS: Expression: B-MYB expression was significantly higher in high-grade tumours (p < 0.0001 and p = 0.048) and in advanced stages (p = 0.005 and p = 0.037) in both cohorts. Correlation: p53-B-MYB as well as MDM2-B-MYB showed significant correlations in local and low-grade ccRCCs, but not in high grade tumours or advanced stages (r < 0.3 and/or p > 0.05). Survival: Multivariable Cox regression of the TCGA cohort revealed B-MYB upregulation and low MDM2 expression as predictors for an impaired overall survival (OS) (HR 1.97; p = 0.0003; HR 2.94, p < 0.0001) and progression-free survival (PFS) (HR 2.86; p = 0.0005; HR 1.58, p = 0.046). In the validation cohort, the results were confirmed for OS by univariable, but not multivariable regression: high B-MYB expression (HR = 3.05, p = 0.035) and low MDM2 expression (HR 3.81, p value 0.036). CONCLUSION: In ccRCC patients with high-grade tumours and advanced stages, high B-MYB expression is common and is associated with poorer OS and PFS. These patients show a loss of their physiological B-MYB-p53 network correlation, suggesting an additional, alternative regulatory, oncogenic mechanism. Assuming further characterization of its signalling pathways, B-MYB could be a potential therapy target for ccRCC.
PURPOSE: To investigate the mRNA expression of B-MYB and MDM2 together with their p53 relatedness in clear cell renal cell carcinoma (ccRCC). METHODS: Genes were screened for their mRNA expression from 529 patients in a publicly available ccRCC cohort (TCGA). A cohort of 101 patients with ccRCC served as validation by qRT-PCR mRNA tissue expression analysis. RESULTS: Expression: B-MYB expression was significantly higher in high-grade tumours (p < 0.0001 and p = 0.048) and in advanced stages (p = 0.005 and p = 0.037) in both cohorts. Correlation: p53-B-MYB as well as MDM2-B-MYB showed significant correlations in local and low-grade ccRCCs, but not in high grade tumours or advanced stages (r < 0.3 and/or p > 0.05). Survival: Multivariable Cox regression of the TCGA cohort revealed B-MYB upregulation and low MDM2 expression as predictors for an impaired overall survival (OS) (HR 1.97; p = 0.0003; HR 2.94, p < 0.0001) and progression-free survival (PFS) (HR 2.86; p = 0.0005; HR 1.58, p = 0.046). In the validation cohort, the results were confirmed for OS by univariable, but not multivariable regression: high B-MYB expression (HR = 3.05, p = 0.035) and low MDM2 expression (HR 3.81, p value 0.036). CONCLUSION: In ccRCC patients with high-grade tumours and advanced stages, high B-MYB expression is common and is associated with poorer OS and PFS. These patients show a loss of their physiological B-MYB-p53 network correlation, suggesting an additional, alternative regulatory, oncogenic mechanism. Assuming further characterization of its signalling pathways, B-MYB could be a potential therapy target for ccRCC.