title: Loss of PBRM1 and BAP1 expression is less common in non-clear cell renal cell carcinoma than in clear cell renal cell carcinoma.
abstract: BACKGROUND
  Recurrent mutations in polybromo-1 (PBRM1, ~40%) and BRCA1-associated protein-1 (BAP1, ~10%) occur in clear cell renal cell carcinoma (ccRCC), but their prevalence in non-ccRCC or renal oncocytoma (RO) is unknown. We evaluated loss of PBRM1 and BAP1 staining in ccRCC, papillary RCC (pRCC), chromophobe RCC (chRCC), and RO tumors using an immunohistochemistry assay in which negative staining was associated with loss-of-function mutations.
  
  
  METHODS
  We identified 458 patients treated surgically for ccRCC, pRCC, chRCC, and RO between 2004 and 2012. We performed immunohistochemistry assays to evaluate PBRM1 and BAP1 protein expression to classify tumors as PBRM1 or BAP1 negative. We compared loss of staining of these 2 proteins in ccRCC and non-ccRCC using the Fisher exact test.
  
  
  RESULTS
  For the total cohort of 458 patients, we successfully stained both PBRM1 and BAP1 in 408 tumor samples. Consistent with the mutation rate, loss of PBRM1 and BAP1 staining occurred in 43% (80/187) and 10% (18/187) of ccRCC cases, respectively. However, loss of PBRM1 staining occurred in only 3% (2/59), 6% (1/17), and 0% (0/34) of pRCC, chRCC, and RO tumors, respectively (P<0.0001). BAP1 loss was not observed in any of the pRCC (n = 61), chRCC (n = 17), or RO (n = 34) tumors, (P = 0.00021).
  
  
  CONCLUSIONS
  Our data suggest that biallelic inactivation of PBRM1 or BAP1 is less common in non-ccRCC when compared with ccRCC tumors. These findings suggest that loss of PBRM1 or BAP1 are key events in ccRCC, whereas other pathways may support tumorigenesis in non-ccRCC subtypes.
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ; Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN. Electronic address: ho.thai@mayo.edu.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX; Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Joseph
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Serie
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL.
authors.forename: Mansi
authors.initials: M
authors.lastname: Parasramka
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: John C
authors.initials: JC
authors.lastname: Cheville
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wu
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Eugene
authors.initials: E
authors.lastname: Frenkel
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX; Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX; Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Karoliina
authors.initials: K
authors.lastname: Stefanius
authors.affiliation: Kidney Cancer Program, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Parker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics
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: BRCA1-associated protein-1; Papillary; Polybromo-1; Renal cell carcinoma