Volume 68, Issue 6, Pages 1016-1020 (December 2015) Survival Prediction of Clear Cell Renal Cell Carcinoma Based on Gene Expression Similarity to the Proximal Tubule of the Nephron  Florian Büttner, Stefan Winter, Steffen Rausch, Anna Reustle, Stephan Kruck, Kerstin Junker, Arnulf Stenzl, Abbas Agaimy, Arndt Hartmann, Jens Bedke, Matthias Schwab, Elke Schaeffeler  European Urology  Volume 68, Issue 6, Pages 1016-1020 (December 2015) DOI: 10.1016/j.eururo.2015.05.045 Copyright © 2015 European Association of Urology Terms and Conditions

Fig. 1 (A) Clustering of renal cell carcinoma (RCC) tumours by means of gene expression correlation between profiles of tumours and profiles of human nephron cell types. Interprofile Spearman rank correlation coefficients (IPCs) were calculated using 97 genes that differentiate nephron regions (glomeruli, initial and terminal part of proximal tubule [S1/S3], medullary and cortical thick ascending limbs of the loop of Henle, distal convoluted tubules, and cortical and outer medullary collecting ducts). The heat map shows z scores obtained by centering and standardising the IPCs per the Cancer Genome Atlas (TCGA) sample. Samples were clustered per tumour entity using a resampling-based consensus clustering approach. Resulting clusters are color coded (see color bar on the left). (B–D) Cancer-specific survival (CSS) of clear cell renal cell carcinoma (ccRCC) tumours predicted by the S3-score. Kaplan-Meier curves showing CSS of (B) the ccRCC cohort (n=463) and (C) the metastatic (n=76) and (D) nonmetastatic subsets (n=374). Groups are defined by cut-offs of the S3-score, as determined by conditional interference tree models. (E) S3-score significantly improves established prediction scores. Chi-square statistic values depict the improvement of the model likelihood when S3-score (red) and ccA/ccB signature (blue) are sequentially added to the Cox model initially including only the stage, size, grade, and necrosis (SSIGN) score. The chi-square statistic comparing the initial model with the null model is given as baseline value (177.73). *p<0.05, **p<0.01, ***p<0.001. (F) Validation of the S3-score in an independent study cohort. Kaplan-Meier curves showing CSS in an independent cohort of ccRCC tumours (n=139) predicted by the S3-score. Groups are defined by the same cut-off value of the S3-score (−0.167) as in (B). Detailed information on statistical methods is given in the supplementary data. CCD=cortical collecting ducts; ccRCC=clear cell renal cell carcinoma; chRCC=chromophobe renal cell carcinoma; CI=confidence interval; CSS=cancer-specific survival; cTAL=cortical thick ascending limbs of the loop of Henle; DCT=distal convoluted tubules; Glom=glomeruli; HR=hazard ratio; IPC=interprofile Spearman rank correlation coefficient; mTAL=medullary thick ascending limbs of the loop of Henle; OMCD=outer medullary collecting ducts; pRCC=papillary renal cell carcinoma; SSIGN=stage, size, grade, and necrosis (score); TCGA=The Cancer Genome Atlas. European Urology 2015 68, 1016-1020DOI: (10.1016/j.eururo.2015.05.045) Copyright © 2015 European Association of Urology Terms and Conditions