title: A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies.
abstract: BACKGROUND
  The likelihood of tumour recurrence after nephrectomy in localised clear cell renal cell carcinoma is well characterised by clinical and pathological parameters. However, these assessments can be improved and personalised by the addition of molecular characteristics of each patient's tumour. We aimed to develop and validate a prognostic multigene signature to improve prediction of recurrence risk in clear cell renal cell carcinoma.
  
  
  METHODS
  In the development stage, we investigated the association between expression of 732 genes, measured by reverse-transcription PCR, and clinical outcome in 942 patients with stage I-III clear cell renal cell carcinoma who had undergone a nephrectomy at the Cleveland Clinic (OH, USA). 516 genes were associated with recurrence-free interval. 11 of these genes were selected by further statistical analyses, and were combined with five reference genes (ie, 16 genes in total), from which a recurrence score algorithm was developed. The recurrence score was then validated in an independent cohort of 626 patients from France with stage I-III clear cell renal cell carcinoma who had also undergone nephrectomy. The association between the recurrence score and the risk of recurrence and cancer-specific survival in the first 5 years after surgery was assessed using Cox proportional hazard regression, stratified by tumour stage (stage I vs stage II vs III).
  
  
  RESULTS
  In our primary univariate analysis, the continuous recurrence score (median 37, IQR 31-45) was significantly associated with recurrence-free interval (hazard ratio 3·91 [95% CI 2·63-5·79] for a 25-unit increase in score, p<0·0001). In multivariable analyses, the recurrence score was significantly associated with the risk of tumour recurrence (hazard ratio per 25-unit increase in the score 3·37 [95% CI 2·23-5·08], p<0·0001) after stratification by stage and adjustment for tumour size, grade, or Leibovich score. The recurrence score was able to identify a clinically significant number of both high-risk stage I and low-risk stage II-III patients. A heterogeneity study on separate samples showed little to no intratumoural variability among the 16 genes.
  
  
  CONCLUSIONS
  Our findings validate the recurrence score as a predictor of clinical outcome in patients with stage I-III clear cell renal cell carcinoma, providing a more accurate and individualised risk assessment beyond existing clinical and pathological parameters.
  
  
  BACKGROUND
  Genomic Health Inc and Pfizer Inc.
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA. Electronic address: rinib2@ccf.org.
authors.forename: Brian
authors.initials: B
authors.lastname: Rini
authors.affiliation: Genomic Health Inc, Redwood City, CA, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Goddard
authors.affiliation: Genomic Health Inc, Redwood City, CA, USA.
authors.forename: Dejan
authors.initials: D
authors.lastname: Knezevic
authors.affiliation: Genomic Health Inc, Redwood City, CA, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Maddala
authors.affiliation: NYU Medical Center, New York, NY, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Singapore General Hospital, Singapore.
authors.forename: Hakan
authors.initials: H
authors.lastname: Aydin
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Campbell
authors.affiliation: Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Koscielny
authors.affiliation: Genomic Health Inc, Redwood City, CA, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Lopatin
authors.affiliation: Genomic Health Inc, Redwood City, CA, USA.
authors.forename: Christer
authors.initials: C
authors.lastname: Svedman
authors.affiliation: Pfizer Inc, San Diego, CA, USA.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Martini
authors.affiliation: Pfizer Inc, San Diego, CA, USA.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Williams
authors.affiliation: Hôpital Necker Enfants Malades, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.affiliation: Hôpital Foch, Suresnes, France.
authors.forename: Camelia
authors.initials: C
authors.lastname: Radulescu
authors.affiliation: Hôpital Foch, Suresnes, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Neuzillet
authors.affiliation: Hôpital Foch, Suresnes, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hemmerlé
authors.affiliation: Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Marc Olivier
authors.initials: MO
authors.lastname: Timsit
authors.affiliation: Genomic Health Inc, Redwood City, CA, USA.
authors.forename: Athanasios C
authors.initials: AC
authors.lastname: Tsiatis
authors.affiliation: Genomic Health Inc, Redwood City, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonham
authors.affiliation: Hôpital Foch, Suresnes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lebret
authors.affiliation: Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Mejean
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D009367:Neoplasm Staging; D009392:Nephrectomy; D011379:Prognosis
chemical_list: D009363:Neoplasm Proteins