title: Survival Prediction of Clear Cell Renal Cell Carcinoma Based on Gene Expression Similarity to the Proximal Tubule of the Nephron.
abstract: There is evidence that molecular features support subclassification of tumours, thereby improving prediction of patient outcome. Currently, two gene expression signatures (ccA/ccB and ClearCode34) have been established to classify clear cell renal cell carcinoma (ccRCC). Because RCC arises from nephron cell types, we aimed to explore its heterogeneity on a molecular level by comparing gene expression between tumour tissue and nephron regions. Based on genes that differ in expression between nephron regions, expression data of 479 ccRCCs and 212 papillary and 66 chromophobe RCCs from The Cancer Genome Atlas were correlated to those of nephron cell types. Cancer-specific survival (CSS) of ccRCC patients was significantly associated with gene expression similarity to the proximal tubules. Subsequently, a ccRCC risk score (S3-score) was established. Survival analyses indicated that the S3-score was significantly associated with CSS considering all cases of ccRCC, as well as metastatic and nonmetastatic ccRCC. Results could be validated in an independent cohort. The S3-score significantly improved the predictive ability of the ccA/ccB and ClearCode34 signatures, and the clinicopathologic-based stage, size, grade, and necrosis score (p [chi-square] = 1.56E-04). Intratumour heterogeneity of the S3-score was observed in 6 of 10 ccRCCs. In summary, the nephron-based S3-score enables prognostic risk stratification for ccRCC. Further studies are needed to evaluate its clinical utility.
  
  
  RESULTS
  We developed a novel risk score for clear cell renal cell carcinoma to identify patients at risk of worse outcome that may improve patient care in the future.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Büttner
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.affiliation: Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Rausch
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Reustle
authors.affiliation: Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kruck
authors.affiliation: Department of Urology and Pediatric Urology, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg/Saar, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Junker
authors.affiliation: Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Stenzl
authors.affiliation: Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.affiliation: Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Urology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Bedke
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany. Electronic address: matthias.schwab@ikp-stuttgart.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality*; D007687:Kidney Tubules, Proximal; D011379:Prognosis
keywords: Biomarker; Nephron; Personalised medicine; Renal cell carcinoma; ccRCC