Signature in Renal Carcinoma Table 1. Cont. Top differentially expressed pathways between early-stage ccRCC and matched normal renal tissues by SigPathway are shown. The pathway signature is characterized by three major biological alterations: downregulation of pathways related to normal renal function, downregulation of metabolic pathways, and immune pathway activation. NTK is a measure of the degree to which a given pathway differs from the other pathways. NEK is a measure of the degree to which the pathway composite expression differs among phenotypes. doi:10.1371/journal.pone.0010696.t001 TFCP2L1 was down-regulated 56-fold and was the most down- regulated transcription factor in ccRCC. Using genes known to be regulated by TFCP2L1 from another study that uses a transgenic mouse model [10], we identified TFCP2L1-regulated genes in our microarray dataset (Fig. 3c). These genes, which mediate epithelial cell development and tubule formation, were present in the normal renal function-related pathways and were down- regulated in ccRCC tissues. It is likely that a loss of TFCP2L1 in ccRCC plays a role in the loss of epithelial differentiation and function in ccRCC. ccRCC is characterized by adipogenic transdifferentiation Since kidneys are mesenchymal in embryonic origin and ccRCC tissues express mesenchymal markers such as vimentin and fibronectin [11], we hypothesized that ccRCC cells have Figure 1. Heatmap signature of clear cell renal cell carcinoma. a. Normal renal function-related pathway gene expression signature. b. Metabolic pathway gene expression signature. c. Immune pathway gene expression signature. Upregulation of genes is indicated in red, downregulation is indicated in green, and a similar expression is indicated in black, as generated by Cluster 3.0. doi:10.1371/journal.pone.0010696.g001 PLoS ONE | www.plosone.org 4 May 2010 | Volume 5 | Issue 5 | e10696