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

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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 - 2014

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BRCA1 Protein
Renal Cell Carcinoma
Proteins
Confidence Intervals
Neoplasms
Necrosis
Immunohistochemistry
Mutation
Survival

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma. / Joseph, Richard W.; Kapur, Payal; Serie, Daniel J.; Eckel-Passow, Jeanette E.; Parasramka, Mansi; Ho, Thai; Cheville, John C.; Frenkel, Eugene P; Rakheja, Dinesh; Brugarolas, James B; Parker, Alexander.

In: Cancer, Vol. 120, No. 7, 2014, p. 1059-1067.

Research output: Contribution to journalArticle

Joseph, Richard W. ; Kapur, Payal ; Serie, Daniel J. ; Eckel-Passow, Jeanette E. ; Parasramka, Mansi ; Ho, Thai ; Cheville, John C. ; Frenkel, Eugene P ; Rakheja, Dinesh ; Brugarolas, James B ; Parker, Alexander. / Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma. In: Cancer. 2014 ; Vol. 120, No. 7. pp. 1059-1067.
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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.",
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author = "Joseph, {Richard W.} and Payal Kapur and Serie, {Daniel J.} and Eckel-Passow, {Jeanette E.} and Mansi Parasramka and Thai Ho and Cheville, {John C.} and Frenkel, {Eugene P} and Dinesh Rakheja and Brugarolas, {James B} and Alexander Parker",
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T1 - Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low-risk clear cell renal cell carcinoma

AU - Joseph, Richard W.

AU - Kapur, Payal

AU - Serie, Daniel J.

AU - Eckel-Passow, Jeanette E.

AU - Parasramka, Mansi

AU - Ho, Thai

AU - Cheville, John C.

AU - Frenkel, Eugene P

AU - Rakheja, Dinesh

AU - Brugarolas, James B

AU - Parker, Alexander

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - BAP1

KW - carcinoma

KW - kidney neoplasms

KW - renal cell

KW - survival

KW - tumor biomarkers

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DO - 10.1002/cncr.28521

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