title: Clear Cell Renal Cell Carcinoma Subtypes Identified by BAP1 and PBRM1 Expression.
abstract: OBJECTIVE
  In clear cell renal cell carcinoma BAP1 and PBRM1 are 2 of the most commonly mutated genes (10% to 15% and 40% to 50%, respectively). We sought to determine the prognostic significance of PBRM1 and BAP1 expression in clear cell renal cell carcinoma.
  
  
  METHODS
  We used immunohistochemistry to assess PBRM1 protein expression in 1,479 primary clear cell renal cell carcinoma tumors that were previously stained for BAP1. A centralized pathologist reviewed all cases and categorized tumors as positive or deficient for PBRM1 and BAP1. Kaplan-Meier and Cox regression models were used to evaluate association of PBRM1 and BAP1 expression with the risk of death from renal cell carcinoma and the risk of metastasis after adjustment for age and the Mayo Clinic SSIGN (stage, size, grade and necrosis) score.
  
  
  RESULTS
  PBRM1 and BAP1 expression was PBRM1+ BAP1+ in 40.1% of tumors, PBRM1- BAP1+ in 48.6%, PBRM1+ BAP1- in 8.7% and PBRM1- BAP1- in 1.8%. The incidence of PBRM1 and BAP1 loss in the same tumor was significantly lower than expected (actual 1.8% vs expected 5.3%, p <0.0001). Compared to patients with PBRM1+ BAP1+ tumors those with PBRM1- BAP1+ lesions were more likely to die of renal cell carcinoma (HR 1.39, p = 0.035), followed by those with PBRM1+ BAP1- and PBRM1- BAP1- tumors (HR 3.25 and 5.2, respectively, each p <0.001). PBRM1 and BAP1 expression did not add independent prognostic information to the SSIGN score.
  
  
  CONCLUSIONS
  PBRM1 and BAP1 expression identified 4 clinical subgroups of patients with clear cell renal cell carcinoma who had divergent clinical outcomes. The clinical value of these biomarkers will be fully realized when therapies targeting pathways downstream of PBRM1 and BAP1 are developed.
authors: Division of Medical Oncology, Departments of Health Sciences Research and Medicine and Division of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Pathology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Internal Medicine and Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota; Division of Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona. Electronic address: joseph.richard@mayo.edu.
authors: Richard W
authors: RW
authors: Joseph
authors: Division of Medical Oncology, Departments of Health Sciences Research and Medicine and Division of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Pathology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Internal Medicine and Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota; Division of Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona.
authors: Payal
authors: P
authors: Kapur
authors: Division of Medical Oncology, Departments of Health Sciences Research and Medicine and Division of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Pathology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Internal Medicine and Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota; Division of Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona.
authors: Daniel J
authors: DJ
authors: Serie
authors: Division of Medical Oncology, Departments of Health Sciences Research and Medicine and Division of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Pathology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Internal Medicine and Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota; Division of Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona.
authors: Mansi
authors: M
authors: Parasramka
authors: Division of Medical Oncology, Departments of Health Sciences Research and Medicine and Division of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Pathology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Internal Medicine and Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota; Division of Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona.
authors: Thai H
authors: TH
authors: Ho
authors: Division of Medical Oncology, Departments of Health Sciences Research and Medicine and Division of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Pathology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Internal Medicine and Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota; Division of Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona.
authors: John C
authors: JC
authors: Cheville
authors: Division of Medical Oncology, Departments of Health Sciences Research and Medicine and Division of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Pathology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Internal Medicine and Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota; Division of Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona.
authors: Eugene
authors: E
authors: Frenkel
authors: Division of Medical Oncology, Departments of Health Sciences Research and Medicine and Division of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Pathology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Internal Medicine and Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota; Division of Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona.
authors: Alexander S
authors: AS
authors: Parker
authors: Division of Medical Oncology, Departments of Health Sciences Research and Medicine and Division of Cancer Biology, Mayo Clinic Florida, Jacksonville, Florida; Department of Pathology, Kidney Cancer Program, Simmons Comprehensive Cancer Center, Division of Hematology-Oncology, Department of Internal Medicine and Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Health Sciences Research, Mayo Clinic Rochester, Rochester, Minnesota; Division of Medical Oncology, Mayo Clinic Arizona, Phoenix, Arizona. Electronic address: james.brugarolas@utsouthwestern.edu.
authors: James
authors: J
authors: Brugarolas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000145:classification* / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000145:classification* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*; D055815:Young Adult
chemical_list: C400134:BAP1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: biological markers; carcinoma; genes; kidney; mortality; renal cell; tumor suppressor