title: Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma.
abstract: BACKGROUND
  The majority of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have low-risk disease with a < 10% chance of ccRCC-specific death. DNA sequencing revealed that mutations in BAP1 (BRCA1 associated protein-1) occur in 5% to 15% of ccRCC cases and are associated with poor outcomes. The vast majority of BAP1 mutations abolish protein expression. In this study, we used a highly sensitive and specific immunohistochemistry (IHC) assay to test whether BAP1 expression is an independent marker of ccRCC-specific survival, particularly in patients with low-risk disease.
  
  
  METHODS
  BAP1 expression was assessed, using IHC, in 1479 patients who underwent nephrectomy to treat clinically localized ccRCC. A centralized pathologist dichotomized patients as either BAP1-positive or BAP1-negative. The authors employed Kaplan-Meier and Cox regression models to associate BAP1 expression with cancer-specific survival.
  
  
  RESULTS
  A total of 10.5% of tumors were BAP1-negative, 84.8% of tumors were BAP1-positive, and 4.6% of tumors had ambiguous staining for BAP1. Patients with BAP1-negative tumors have an increased risk of ccRCC-related death (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 2.28-4.10; P = 6.77 × 10(-14) ). BAP1 expression remained an independent marker of prognosis after adjusting for the UCLA integrated staging system (UISS) (HR = 1.67; 95% CI = 1.24-2.25; P < .001). Finally, BAP1 was an independent prognostic marker in low-risk patients with a Mayo Clinic stage, size, grade, and necrosis (SSIGN) score of ≤ 3 (HR = 3.24; 95% CI = 1.26-8.33; P = .015).
  
  
  CONCLUSIONS
  This study used a large patient cohort to demonstrate that BAP1 expression is an independent marker of prognosis in patients with low-risk (SSIGN≤ 3) ccRCC.
authors.affiliation: Division of Medical Oncology, Mayo Clinic Florida, Jacksonville, Florida.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Joseph
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Serie
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.forename: Mansi
authors.initials: M
authors.lastname: Parasramka
authors.forename: Thai
authors.initials: T
authors.lastname: Ho
authors.forename: John C
authors.initials: JC
authors.lastname: Cheville
authors.forename: Eugene
authors.initials: E
authors.lastname: Frenkel
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
authors.forename: Alexander
authors.initials: A
authors.lastname: Parker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: BAP1; carcinoma; kidney neoplasms; renal cell; survival; tumor biomarkers