title: Molecular Stratification of Clear Cell Renal Cell Carcinoma by Consensus Clustering Reveals Distinct Subtypes and Survival Patterns.
abstract: Clear cell renal cell carcinoma (ccRCC) is the predominant RCC subtype, but even within this classification, the natural history is heterogeneous and difficult to predict. A sophisticated understanding of the molecular features most discriminatory for the underlying tumor heterogeneity should be predicated on identifiable and biologically meaningful patterns of gene expression. Gene expression microarray data were analyzed using software that implements iterative unsupervised consensus clustering algorithms to identify the optimal molecular subclasses, without clinical or other classifying information. ConsensusCluster analysis identified two distinct subtypes of ccRCC within the training set, designated clear cell type A (ccA) and B (ccB). Based on the core tumors, or most well-defined arrays, in each subtype, logical analysis of data (LAD) defined a small, highly predictive gene set that could then be used to classify additional tumors individually. The subclasses were corroborated in a validation data set of 177 tumors and analyzed for clinical outcome. Based on individual tumor assignment, tumors designated ccA have markedly improved disease-specific survival compared to ccB (median survival of 8.6 vs 2.0 years, P = 0.002). Analyzed by both univariate and multivariate analysis, the classification schema was independently associated with survival. Using patterns of gene expression based on a defined gene set, ccRCC was classified into two robust subclasses based on inherent molecular features that ultimately correspond to marked differences in clinical outcome. This classification schema thus provides a molecular stratification applicable to individual tumors that has implications to influence treatment decisions, define biological mechanisms involved in ccRCC tumor progression, and direct future drug discovery.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.forename: Anupama
authors.initials: A
authors.lastname: Reddy
authors.forename: Michael
authors.initials: M
authors.lastname: Seiler
authors.forename: Alexandra
authors.initials: A
authors.lastname: Arreola
authors.forename: Dominic T
authors.initials: DT
authors.lastname: Moore
authors.forename: Raj S
authors.initials: RS
authors.lastname: Pruthi
authors.forename: Eric M
authors.initials: EM
authors.lastname: Wallen
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Nielsen
authors.forename: Huiqing
authors.initials: H
authors.lastname: Liu
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Börje
authors.initials: B
authors.lastname: Ljungberg
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zhao
authors.forename: James D
authors.initials: JD
authors.lastname: Brooks
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Gyan
authors.initials: G
authors.lastname: Bhanot
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell