title: Higher expression of topoisomerase II alpha is an independent marker of increased risk of cancer-specific death in patients with clear cell renal cell carcinoma.
abstract: BACKGROUND
  Tumor-based biomarkers of outcome for patients with clear cell renal cell carcinoma (ccRCC) remain limited, especially for those with low-risk disease. Type IIa topoisomerase (TOPOIIa) is a well-known biomarker of DNA replication and a target for antineoplastic agents, but it has not been evaluated as a biomarker of ccRCC outcome.
  
  
  OBJECTIVE
  To evaluate the association of TOPOIIa expression in ccRCC and risk of cancer-specific death following surgery.
  
  
  METHODS
  Two independent cohort studies were studied in tertiary referral urology practices in the United States. We identified cohorts of 1378 (analytic) and 279 (validation) patients who underwent nephrectomy for clinically localized ccRCC and had paraffin tumor tissue available. TOPOIIa expression was assessed using immunohistochemistry and scored as the number of positive cells per square millimeter.
  
  
  METHODS
  Our primary end point was cancer-specific survival (CSS). We evaluated TOPOIIa expression as a continuous variable and dichotomized as low versus high. For associations with CSS, we used Kaplan-Meier curves and Cox regression models.
  
  
  CONCLUSIONS
  In both cohorts, patients who had high TOPOIIa expression were approximately three times more likely to experience ccRCC death than those with low expression (hazard ratio [HR]: 2.75; 95% confidence interval [CI], 2.12-3.56; p=1.79E-14 and HR: 3.45; 95% CI, 1.34-8.88; p=0.0104, respectively). Multivariable adjustment for pathologic features of aggressiveness did not explain these associations, and stratified analysis suggests that the association is more pronounced among patients with low-risk disease as defined by the Mayo Clinic SSIGN (stage, size, grade, and necrosis) score.
  
  
  CONCLUSIONS
  Higher TOPOIIa expression is independently associated with increased risk of cancer death among patients undergoing surgery for ccRCC, and the prognostic value is pronounced among patients with low-risk disease. Evaluation of TOPOIIa in ccRCC provides the opportunity to help guide postsurgical surveillance for ccRCC patients as well as inform the design of more targeted clinical trials and novel treatment strategies.
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA. Electronic address: parker.alexander@mayo.edu.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Parker
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Serie
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Hilton
authors.affiliation: Department of Cancer Basic Science, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Mansi
authors.initials: M
authors.lastname: Parasramka
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Joseph
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wu
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Cheville
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Leibovich
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001706:Biopsy; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D004250:DNA Topoisomerases, Type II / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000032:analysis*; D005260:Female; D005431:Florida; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D015999:Multivariate Analysis; D009336:Necrosis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009392:Nephrectomy / Q000009:adverse effects / Q000401:mortality*; D015588:Observer Variation; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012042:Registries; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D062606:Tertiary Care Centers; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D004250:DNA Topoisomerases, Type II
keywords: Biologic; Carcinoma, renal cell; Kidney neoplasms; Survival; Tumor biomarkers