title: Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities.
abstract: OBJECTIVE
  The 34-gene classifier, ClearCode34, identifies prognostically distinct molecular subtypes of clear cell renal cell carcinoma (ccRCC) termed clear cell A (ccA) and clear cell B (ccB). The primary objective of this study was to describe clinical characteristics and comorbidities of relevance in patients stratified by ClearCode34.
  
  
  METHODS
  In this retrospective analysis, 282 patients from Moffitt Cancer Center with ccRCC with gene expression analyses of the primary tumor were identified and ClearCode34 was applied to identify tumors as ccA or ccB. The medical record and institutional databases were queried to define patient characteristics, comorbidities, and outcomes.
  
  
  RESULTS
  We validated in this external cohort the superior overall survival, cancer-specific survival, and recurrence-free survival of ccA patients relative to ccB patients (P<0.001). Addressing other clinical characteristics, the ccA patients were more likely to be obese (48% vs. 34%, P = 0.021) and diabetic (26% vs. 13%, P = 0.035). The ccA patients also trended toward having been more frequent users of angiotensin system inhibitors (71% vs. 52%, P = 0.055). In multivariate analyses, ccB status is independently associated with inferior cancer-specific survival (hazard ratio = 3.26, 95% confidence interval: 1.84-5.79) and overall survival (hazard ratio = 2.50, 95% confidence interval: 1.53-4.08).
  
  
  CONCLUSIONS
  ClearCode34, after considering distinct patterns of comorbidities in each molecular subtype, remains a strong prognostic tool in patients with ccRCC. Obesity and diabetes mellitus emerged as factors that may influence ccRCC phenotypes and further studies investigating the effect of these metabolic conditions functionally onto tumor biology are warranted. Additionally, use of angiotensin system inhibitors could be studied in the context of ccRCC molecular classification in future studies to better understand its effect on ccRCC outcomes.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. Electronic address: Scott.M.Haake@Vanderbilt.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Haake
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Samira A
authors.initials: SA
authors.lastname: Brooks
authors.affiliation: Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Eric
authors.initials: E
authors.lastname: Welsh
authors.affiliation: Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Fulp
authors.affiliation: Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.affiliation: Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Jasreman
authors.initials: J
authors.lastname: Dhillon
authors.affiliation: Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
authors.forename: Eric
authors.initials: E
authors.lastname: Haura
authors.affiliation: Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
authors.forename: Wade
authors.initials: W
authors.lastname: Sexton
authors.affiliation: Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
authors.forename: Philippe E
authors.initials: PE
authors.lastname: Spiess
authors.affiliation: Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
authors.forename: Julio
authors.initials: J
authors.lastname: Pow-Sang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
authors.affiliation: Genitourinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL. Electronic address: Mayer.Fishman@Moffitt.org.
authors.forename: Mayer
authors.initials: M
authors.lastname: Fishman
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000145:classification / Q000235:genetics* / Q000556:secondary; D015897:Comorbidity; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007680:Kidney Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000145:classification / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor
keywords: Clear cell renal cell carcinoma; ClearCode34; Diabetes mellitus; Obesity