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

• Published in: Cancer Vol. 120; no. 7; pp. 1059 - 1067
• Main Authors: Joseph, Richard W., Kapur, Payal, Serie, Daniel J., Eckel‐Passow, Jeanette E., Parasramka, Mansi, Ho, Thai, Cheville, John C., Frenkel, Eugene, Rakheja, Dinesh, Brugarolas, James, Parker, Alexander
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 01.04.2014
• Subjects: Adult; Aged; Aged, 80 and over; BAP1; Biological and medical sciences; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; carcinoma; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Cohort Studies; Female; Humans; Immunohistochemistry; kidney neoplasms; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidneys; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; Prognosis; renal cell; Risk Factors; survival; Survival Analysis; tumor biomarkers; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics; Tumors; Tumors of the urinary system; Ubiquitin Thiolesterase - biosynthesis; Ubiquitin Thiolesterase - genetics; Kidney disease; Human; Urinary system disease; Mesonephroma; Prognosis; tumor biomarkers; Biological marker; Malignant tumor; Survival; Low risk; Protein; Kidney; Clear cell carcinoma; renal cell; Cancerology; Urinary system; carcinoma; Kidney cancer; Grawitz tumor; kidney neoplasms; Cell; BAP1; Cancer; Tumor suppressor gene; survival
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.28521

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. Cancer 2014;1059–1067. © 2014 American Cancer Society. BAP1 (BRCA1 associated protein‐1) is mutated in ∼10% of clear cell renal cell carcinomas (ccRCC), and BAP1 mutations lead to decreased expression of the protein. This study demonstrates that loss of BAP1 protein is independently associated with decreased survival in patients with low‐risk ccRCC.