BAP1 and PBRM1 in metastatic clear cell renal cell carcinoma: tumor heterogeneity and concordance with paired primary tumor.
BACKGROUND
BAP1 and PBRM1 are frequently mutated in primary clear cell renal cell carcinoma (ccRCC) tumors; however, the frequency and clinical relevance of these mutations in metastatic ccRCC tumors is unknown. Additionally, while intra-tumor heterogeneity has been shown to be common in primary ccRCC, little is known regarding heterogeneity in metastatic ccRCC tumors.


METHODS
We analyzed BAP1 and PBRM1 loss of protein expression in patient-matched primary and metastatic tumors from 97 patients. Expression was determined using a validated immunohistochemistry assay, which has been shown to be correlated with mutation status.


RESULTS
Of the 97 patients evaluated, 20 and 57% showed loss of BAP1 and PBRM1 in their primary tumors, respectively. Comparing expression across patient-matched primary-metastatic tumor pairs, 98 and 90% had concordant BAP1 and PBRM1 expression, respectively. Both patients who demonstrated discordant BAP1 expression showed loss of BAP1 expression during progression to metastatic ccRCC. Similarly, seven of the ten patients that demonstrated discordant PBRM1 expression showed loss of PBRM1 expression during progression to metastatic ccRCC. We evaluated intra-metastatic tumor heterogeneity using 12 patients who had multiple blocks available from the same tumor with representative pathology; 100 and 92% showed concordant BAP1 and PBRM1 expression, respectively. Amongst 32 patients who had serial metastatic tumors available, both BAP1 and PBRM1 had 97% concordant expression.


CONCLUSIONS
We observed minimal intra- and inter- tumor heterogeneity in metastatic ccRCC tumors. Patients with discordant BAP1 or PBRM1 expression across their matched primary and metastatic tumors usually showed loss of expression during progression to metastatic ccRCC.
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
Jeanette E
JE
Eckel-Passow
Department of Health Sciences Research, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Daniel J
DJ
Serie
Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
John C
JC
Cheville
Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.
Thai H
TH
Ho
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Payal
P
Kapur
Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
James
J
Brugarolas
Department of Urology, Mayo Clinic, Rochester, MN, USA.
R Houston
RH
Thompson
Department of Urology, Mayo Clinic, Rochester, MN, USA.
Bradley C
BC
Leibovich
Department of Urology, Mayo Clinic, Rochester, MN, USA.
Eugene D
ED
Kwon
Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
Richard W
RW
Joseph
Department of Health Sciences Research, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. parker.alexander@mayo.edu.
Alexander S
AS
Parker
D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000556:secondary; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
C400134:BAP1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
Clonal; Immunohistochemistry; Prognostic