BAP1 immunohistochemistry predicts outcomes in a multi-institutional cohort with clear cell renal cell carcinoma.
OBJECTIVE
Mutations in the tumor suppressor gene BAP1 occur in approximately 15% of clear cell renal cell carcinoma cases. Sequencing efforts demonstrated worse outcomes in patients with BAP1 mutated clear cell renal cell carcinoma. We investigated the clinicopathological significance and oncologic outcomes of BAP1 loss using a previously validated immunohistochemical assay.


METHODS
Immunohistochemistry for BAP1 was performed on tissue microarray sections from 559 nonmetastatic clear cell renal cell carcinoma cases treated with nephrectomy at multiple institutions. The association of BAP1 expression with clinicopathological parameters was analyzed using the Wilcoxon rank sum and Cochran-Mantel-Haenszel tests. Survival was assessed by Cox regression analysis, which also identified independent predictors of time dependent outcomes.


RESULTS
At a median followup of 50 months (range 0 to 183) 86 of 483 patients (17.8%) experienced recurrence and 121 of 559 (21.6%) had died. BAP1 was negative in 82 of 559 tumors (14.7%). BAP1 loss was associated with adverse clinicopathological variables, including high Fuhrman grade (p <0.0001), advanced pT stage (p = 0.0021), sarcomatoid dedifferentiation (p = 0.0001) and necrosis (p <0.0001). Cox regression revealed that patients with BAP1 negative tumors had significantly worse disease-free survival (HR 2.9, 95% CI 1.8-4.7, p <0.0001) and overall survival (HR 2.0, 95% CI 1.3-3.1, p = 0.0010) than patients with BAP1 positive tumors.


CONCLUSIONS
Immunohistochemistry for BAP1 serves as a powerful marker to predict poor oncologic outcomes and adverse clinicopathological features in patients with nonmetastatic clear cell renal cell carcinoma. BAP1 assessment using immunohistochemistry on needle biopsy may benefit preoperative risk stratification and guide treatment planning in the future.
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France. Electronic address: payal.kapur@utsouthwestern.edu.
Payal
P
Kapur
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Alana
A
Christie
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Jay D
JD
Raman
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Matthew T
MT
Then
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Philipp
P
Nuhn
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Alexander
A
Buchner
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Patrick
P
Bastian
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Christian
C
Seitz
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Shahrokh F
SF
Shariat
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Karim
K
Bensalah
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Nathalie
N
Rioux-Leclercq
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Xian-Jin
XJ
Xie
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Yair
Y
Lotan
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
Vitaly
V
Margulis
Department of Pathology (PK), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology (PK, YL, VM), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Internal Medicine (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Developmental Biology (JB), University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center (XJX, JB), University of Texas Southwestern Medical Center, Dallas, Texas; Department of Urology, Penn State Milton S. Hershey Medical Center (JDR), Hershey, Pennsylvania; Department of Pathology, University of Pittsburgh Medical Center (MTT), Pittsburgh, Pennsylvania; Department of Urology, University of Munich (PN, AB), Munich, Germany; Department of Urology, Paracelsus-Klinik Golzheim, Dusseldorf, Germany (PB); Department of Urology, Central Hospital of Bolzano (CS), Bolzano, Italy; Department of Urology, Medical University of Vienna, Vienna General Hospital (CS, SFS), Vienna, Austria; Department of Urology and Pathology, University of Rennes (KB, NR-L), Rennes, France.
James
J
Brugarolas
D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D012306:Risk; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
BAP1 protein; carcinoma; human; kidney; prognosis; renal cell; risk