title: Impact of recurrent copy number alterations and cancer gene mutations on the predictive accuracy of prognostic models in clear cell renal cell carcinoma.
abstract: OBJECTIVE
  Several recently reported recurrent genomic alterations in clear cell renal cell carcinoma are linked to pathological and clinical outcomes. We determined whether any recurrent cancer gene mutations or copy number alterations identified in the TCGA (The Cancer Genome Atlas) clear cell renal cell carcinoma data set could add to the predictive accuracy of current prognostic models.
  
  
  METHODS
  In 413 patients who underwent nephrectomy/partial nephrectomy we investigated whole exome, copy number array analyses and clinical variables. We identified 65 recurrent genomic alterations based on prevalence and combined them into 35 alterations, including 12 cancer gene mutations. Genomic markers were modeled using the elastic net algorithm with preoperative variables (tumor size plus patient age) and in the postoperative setting using the externally validated Mayo Clinic SSIGN (stage, size, grade and necrosis) prognostic scoring system. These models were subjected to internal validation using bootstrap.
  
  
  RESULTS
  Median followup in survivors was 45 months. Several markers correlated with adverse cancer specific survival and time to recurrence on univariate analysis. However, most of them lost significance when controlling for tumor size with or without age in the preoperative models or for SSIGN score in the postoperative setting. Adding multiple genomic markers selected by the elastic net algorithm failed to substantially add to the predictive accuracy of any preoperative or postoperative model for cancer specific survival or time to recurrence.
  
  
  CONCLUSIONS
  While recurrent copy number alterations and cancer gene mutations are biologically significant, they do not appear to improve the predictive accuracy of existing models of clinical cancer specific survival or time to recurrence for clear cell renal cell carcinoma.
authors: Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York. Electronic address: hakimia@mskcc.org.
authors: A Ari
authors: AA
authors: Hakimi
authors: Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Roy
authors: R
authors: Mano
authors: Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Giovanni
authors: G
authors: Ciriello
authors: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Mithat
authors: M
authors: Gonen
authors: Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Nina
authors: N
authors: Mikkilineni
authors: Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: John P
authors: JP
authors: Sfakianos
authors: Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Philip H
authors: PH
authors: Kim
authors: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Robert J
authors: RJ
authors: Motzer
authors: Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Paul
authors: P
authors: Russo
authors: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Victor E
authors: VE
authors: Reuter
authors: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: James J
authors: JJ
authors: Hsieh
authors: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors: Irina
authors: I
authors: Ostrovnaya
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D011379:Prognosis; D015203:Reproducibility of Results; D012189:Retrospective Studies; D015996:Survival Rate
keywords: DNA copy number variations; DNA mutational analysis; carcinoma; kidney; prognosis; renal cell