Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma

Richard W. Joseph, Payal Kapur, Daniel J. Serie, Jeanette E. Eckel-Passow, Mansi Parasramka, Thai Ho, John C. Cheville, Eugene P Frenkel, Dinesh Rakheja, James B Brugarolas, Alexander Parker

Research output: Contribution to journalArticle

75 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1059-1067
Number of pages9
JournalCancer
Volume120
Issue number7
DOIs
StatePublished - Jan 1 2014

Keywords

  • BAP1
  • carcinoma
  • kidney neoplasms
  • renal cell
  • survival
  • tumor biomarkers

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Joseph, R. W., Kapur, P., Serie, D. J., Eckel-Passow, J. E., Parasramka, M., Ho, T., Cheville, J. C., Frenkel, E. P., Rakheja, D., Brugarolas, J. B., & Parker, A. (2014). Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma. Cancer, 120(7), 1059-1067. https://doi.org/10.1002/cncr.28521