title: Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and Aggressiveness.
abstract: Intratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored.
  
  
  
  To evaluate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC tumors.
  
  
  
  We identified 111 patients who had tissue available from their primary tumor and at least one metastasis. ClearCode34 genes were analyzed for all tumors.
  
  
  
  Primary and metastatic tumors were classified as clear cell type A (ccA) or B (ccB) subtypes. Logistic and Cox regression were used to evaluate associations with pathologic features and survival.
  
  
  
  Intratumor heterogeneity of ccA/ccB subtypes was observed in 22% (95% confidence interval [CI] 3-60%) of metastatic tumors. Subtype differed across longitudinal metastatic tumors from the same patient in 23% (95% CI 10-42%) of patients and across patient-matched primary and metastatic tumors in 43% (95% CI 32-55%) of patients. Association of subtype with survival was validated in primary ccRCC tumors. The ccA/ccB subtype in metastatic tumors was significantly associated with metastatic tumor location, metastatic tumor grade, and presence of tumor necrosis. A limitation of this study is that we only analyzed patients who had both a nephrectomy and metastasectomy.
  
  
  
  Approximately one quarter of metastatic tumors displayed intratumor heterogeneity; a similar rate of heterogeneity was observed across longitudinal metastatic tumors. Thus, for biomarker studies it is likely adequate to analyze a single sample per metastatic tumor provided that pathologic review is incorporated into the study design. Subtypes across patient-matched primary and metastatic tumors differed 43% of the time, suggesting that the primary tumor is not a good surrogate for the metastatic tumor.
  
  
  
  Primary and secondary/metastatic cancers of the kidney differed in nearly one half of ccRCC patients. The pattern of this relationship may affect tumor growth and the most suitable treatment.
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Serie
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Joseph
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Cheville
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Mansi
authors.initials: M
authors.lastname: Parasramka
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 Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: R Houston
authors.initials: RH
authors.lastname: Thompson
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Leibovich
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Parker
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA. Electronic address: eckelpassow.jeanette@mayo.edu.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000145:classification / Q000235:genetics* / Q000556:secondary / Q000601:surgery; D005260:Female; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016015:Logistic Models; D008297:Male; D059146:Metastasectomy; D008875:Middle Aged; D009336:Necrosis; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009392:Nephrectomy; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor
keywords: Biomarker; ClearCode34; Formalin-fixed; Kidney; Subtype; paraffin-embedded tissue