title: ClearCode34: A prognostic risk predictor for localized clear cell renal cell carcinoma.
abstract: BACKGROUND
  Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting.
  
  
  OBJECTIVE
  To generate a signature biomarker for the clear cell renal cell carcinoma (ccRCC) good risk (ccA) and poor risk (ccB) subtype classification that could be readily applied to clinical samples to develop an integrated model for biologically defined risk stratification.
  
  
  METHODS
  A set of 72 ccRCC sample standards was used to develop a 34-gene classifier (ClearCode34) for assigning ccRCC tumors to subtypes. The classifier was applied to RNA-sequencing data from 380 nonmetastatic ccRCC samples from the Cancer Genome Atlas (TCGA), and to 157 formalin-fixed clinical samples collected at the University of North Carolina.
  
  
  METHODS
  Kaplan-Meier analyses were performed on the individual cohorts to calculate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Training and test sets were randomly selected from the combined cohorts to assemble a risk prediction model for disease recurrence.
  
  
  CONCLUSIONS
  The subtypes were significantly associated with RFS (p<0.01), CSS (p<0.01), and OS (p<0.01). Hazard ratios for subtype classification were similar to those of stage and grade in association with recurrence risk, and remained significant in multivariate analyses. An integrated molecular/clinical model for RFS to assign patients to risk groups was able to accurately predict CSS above established, clinical risk-prediction algorithms.
  
  
  CONCLUSIONS
  The ClearCode34-based model provides prognostic stratification that improves upon established algorithms to assess risk for recurrence and death for nonmetastatic ccRCC patients.
  
  
  RESULTS
  We developed a 34-gene subtype predictor to classify clear cell renal cell carcinoma tumors according to ccA or ccB subtypes and built a subtype-inclusive model to analyze patient survival outcomes.
authors.affiliation: UNC Lineberger Cancer Center, Chapel Hill, NC, USA.
authors.forename: Samira A
authors.initials: SA
authors.lastname: Brooks
authors.affiliation: UNC Lineberger Cancer Center, Chapel Hill, NC, USA; Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.affiliation: UNC Lineberger Cancer Center, Chapel Hill, NC, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.affiliation: UNC Lineberger Cancer Center, Chapel Hill, NC, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Fisher
authors.affiliation: UNC Lineberger Cancer Center, Chapel Hill, NC, USA.
authors.forename: Oishee
authors.initials: O
authors.lastname: Sen
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Kattan
authors.affiliation: Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.affiliation: Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
authors.affiliation: Department of Medical Oncology and Kidney Cancer Center, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Pheroze
authors.initials: P
authors.lastname: Tamboli
authors.affiliation: Department of Urologic Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Jodi K
authors.initials: JK
authors.lastname: Maranchie
authors.affiliation: Department of Urologic Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hinds
authors.affiliation: UNC Lineberger Cancer Center, Chapel Hill, NC, USA; Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.affiliation: UNC Lineberger Cancer Center, Chapel Hill, NC, USA; Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Nielsen
authors.affiliation: UNC Lineberger Cancer Center, Chapel Hill, NC, USA; Department of Medicine, Division of Hematology and Oncology, and Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: Rathmell@med.unc.edu.
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000145:classification / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007680:Kidney Neoplasms / Q000145:classification / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D012334:RNA, Neoplasm / Q000032:analysis; D018570:Risk Assessment; D017423:Sequence Analysis, RNA; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D012334:RNA, Neoplasm
keywords: Biomarker; Kidney cancer; Prognosis; Renal cell carcinoma; TCGA; ccRCC