Use of meta-analysis of clear cell renal cell carcinoma gene expression to define a variant subgroup and identify gender influences on tumor biology.

Abstract

412 Background: Clear cell renal cell carcinoma (ccRCC) displays molecular and histological heterogeneity. Previously described subsets of this disease, ccA and ccB, were defined based on multi-gene expression profiles, but it is unclear if these subgroupings reflect the full spectrum of disease or how these molecular subtypes relate to histological descriptions or gender. We sought to determine whether additional subtypes of ccRCC exist, and whether these subtypes are related to VHL inactivation, HIF1/HIF2 expression, tumor histology, or gender. Methods: Six large publically available ccRCC gene expression databases were identified that cumulatively provided data for 480 tumors for meta-analysis via meta-array compilation. 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: Two dominant subsets of ccRCC were observed. However, a minor third cluster was revealed which correlated strongly with a wild type VHL expression profile and indications of variant histologies. When variant histologies were removed, ccA tumors naturally divided by gender. This technique is limited by potential for persistent batch effect, tumor sampling bias, and restrictions of annotated information. Conclusions: ccA and ccB subsets of ccRCC are robust in meta-analysis among histologically conventional ccRCC tumors. A third group of tumors was identified, which may represent a new variant of ccRCC. Within definitively clear cell tumors, gender may delineate tumors in such a way that could have implications regarding current treatments and future drug development.