title: Prognostic role of cell cycle and proliferative biomarkers in patients with clear cell renal cell carcinoma.
abstract: OBJECTIVE
  Cell cycle regulatory molecules are implicated in various stages of carcinogenesis. In this proof of principle study we systematically evaluate the association of aberrant expression of cell cycle regulators and proliferative markers and their effect on oncologic outcomes of patients with clear cell renal carcinoma.
  
  
  METHODS
  Immunohistochemistry for Cyclin D, Cyclin E, p16, p21, p27, p53, p57 and Ki67 was performed on tissue microarray constructs of 452 patients treated with extirpative therapy for clear cell renal cell carcinoma between 1997 and 2010. Clinical and pathological data elements were collected. A prognostic marker score was defined as unfavorable if more than 4 biomarkers were altered. The relationship between marker score and pathological features and oncologic outcomes was evaluated.
  
  
  RESULTS
  Median age was 57 years (range 17 to 85) and median followup was 24 months (range 6 to 150). An unfavorable marker score was found in 55 (12.2%) patients and was associated with adverse pathological features. A significant correlation between unfavorable marker score and disease-free survival (HR 26.62, 95% CI 43.38-100.04, p=0.000) and with cancer specific survival (HR 8.15, 95% CI 74.42-101.56, p=0.004) was demonstrated on Kaplan-Meier survival analysis. On multivariate analysis an unfavorable marker score was an independent predictor of disease-free survival (HR 2.63, 95% CI 1.08-6.38, p=0.033).
  
  
  CONCLUSIONS
  The cumulative number of aberrantly expressed cell cycle and proliferative biomarkers correlates with aggressive pathological features and inferior oncologic outcomes in patients with clear cell renal cell carcinoma. Our findings indicate that interrogation of cell cycle and proliferative markers is feasible, and further prospective pathway based exploration of biomarkers is needed.
authors.affiliation: Departments of Urology and Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Bishoy A
authors.initials: BA
authors.lastname: Gayed
authors.forename: Ramy F
authors.initials: RF
authors.lastname: Youssef
authors.forename: Aditya
authors.initials: A
authors.lastname: Bagrodia
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.forename: Oussama M
authors.initials: OM
authors.lastname: Darwish
authors.forename: Laura-Maria
authors.initials: LM
authors.lastname: Krabbe
authors.forename: Arthur
authors.initials: A
authors.lastname: Sagalowsky
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.forename: Vitaly
authors.initials: V
authors.lastname: Margulis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000737:chemistry / Q000473:pathology*; D002453:Cell Cycle; D006801:Humans; D007680:Kidney Neoplasms / Q000737:chemistry / Q000473:pathology*; D008875:Middle Aged; D011379:Prognosis; D055815:Young Adult
chemical_list: D015415:Biomarkers
keywords: CDK; CSS; DFS; MS; RCC; biological markers; cancer specific survival; carcinoma; ccRCC; cell cycle proteins; clear cell renal cell carcinoma; cyclin dependent kinase; disease-free survival; marker score; prognosis; renal cell; renal cell carcinoma