Meta-analysis of Clear Cell Renal Cell Carcinoma Gene Expression Defines a Variant Subgroup and Identifies Gender Influences on Tumor Biology

• Published in: European urology 2012-02, Vol.61 (2), p.258-268
• Main Authors: Brannon, A. Rose, Haake, Scott M, Hacker, Kathryn E, Pruthi, Raj S, Wallen, Eric M, Nielsen, Matthew E, Rathmell, W. Kimryn
• Format: Article
• Language: English
• Subjects: Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Clear cell renal cell carcinoma; Cluster Analysis; Female; Gender; Gene expression; Gene Expression Regulation, Neoplastic; HIF; Humans; Hypoxia; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - metabolism; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Male; Medical sciences; Nephrology. Urinary tract diseases; RCC; Renal cell carcinoma; Sex Factors; Tumors of the urinary system; Urology; VHL; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2011.10.007

Abstract Background Clear cell renal cell carcinoma (ccRCC) displays molecular and histologic heterogeneity. Previously described subsets of this disease, ccA and ccB, were defined based on multigene expression profiles, but it is unclear whether these subgroupings reflect the full spectrum of disease or how these molecular subtypes relate to histologic descriptions or gender. Objective Determine whether additional subtypes of ccRCC exist and whether these subtypes are related to von Hippel-Lindau (VHL) inactivation, hypoxia-inducible factor (HIF) 1 and 2 expression, tumor histology, or gender. Design, setting, and participants Six large, publicly available ccRCC gene expression databases were identified that cumulatively provided data for 480 tumors for meta-analysis via meta-array compilation. Measurements Unsupervised consensus clustering was performed on the meta-arrays. Tumors were examined for the relationship of multigene-defined consensus subtypes and expression signatures of VHL mutation and HIF status, tumor histology, and gender. Results and limitations Two dominant subsets of ccRCC were observed. However, a minor third cluster was revealed that correlated strongly with a wild type (WT) VHL expression profile and indications of variant histologies. When variant histologies were removed, ccA tumors naturally divided by gender. This technique is limited by the potential for persistent batch effect, tumor sampling bias, and restrictions of annotated information. Conclusions The ccA and ccB subsets of ccRCC are robust in meta-analysis among histologically conventional ccRCC tumors. A third group of tumors was identified that may represent a new variant of ccRCC. Within definitively clear cell tumors, gender may delineate tumors in such a way that it could have implications regarding current treatments and future drug development.