Involvement of PBRM1 in VHL disease‑associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway

Gad,Sophie; Le Teuff,Gwenaël; Nguyen,Baptiste; Verkarre,Virginie; Duchatelle,Veronique; Molinie,Vincent; Posseme,Katia; Grandon,Benjamin; Da Costa,Melanie; Job,Bastien; Meurice,Guillaume; Droin,Nathalie; Mejean,Arnaud; Couve,Sophie; Renaud,Flore; Gardie,Betty; Teh,Bin Tean; Richard,Stephane; Ferlicot,Sophie

doi:10.3892/ol.2021.13096

Involvement of PBRM1 in VHL disease‑associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway

Authors:
- Sophie Gad
- Gwenaël Le Teuff
- Baptiste Nguyen
- Virginie Verkarre
- Veronique Duchatelle
- Vincent Molinie
- Katia Posseme
- Benjamin Grandon
- Melanie Da Costa
- Bastien Job
- Guillaume Meurice
- Nathalie Droin
- Arnaud Mejean
- Sophie Couve
- Flore Renaud
- Betty Gardie
- Bin Tean Teh
- Stephane Richard
- Sophie Ferlicot
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Affiliations: Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences Lettres Research University, 75014 Paris, France, Department of Biostatistics and Epidemiology, Gustave Roussy Institute, CNRS, Paris‑Saclay University, 94800 Villejuif, France, Department of Pathology, Public Hospitals of Paris (AP‑HP) Centre, Georges Pompidou European Hospital, Paris University, 75015 Paris, France, Department of Pathology, Saint‑Joseph Hospital, 75014 Paris, France, Department of Pathology, AP‑HP, Bicêtre Hospital, Paris‑Saclay University, 94270 Le Kremlin‑Bicêtre, France, Bioinformatics Core Facility, Gustave Roussy Institute, CNRS, Paris‑Saclay University, 94800 Villejuif, France, Genomics Core Facility, Gustave Roussy Institute, CNRS, Paris‑Saclay University, 94800 Villejuif, France, Department of Urology, PREDIR French National Cancer Institute (INCa), AP‑HP, Bicêtre Hospital, 94270 Le Kremlin‑Bicêtre, France, Program in Cancer and Stem Cell Biology, Duke‑National University of Singapore (NUS) Medical School, Singapore 169610, Republic of Singapore, Mixed Research Unit (UMR) 9019, Gustave Roussy Institute, French National Scientific Research Center (CNRS), Paris‑Saclay University, 94800 Villejuif, France
Published online on: October 15, 2021 https://doi.org/10.3892/ol.2021.13096
Article Number: 835
Copyright: © Gad et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Von Hippel‑Lindau (VHL) disease is the main cause of inherited clear‑cell renal cell carcinoma (ccRCC) and is caused by germline mutations in the VHL tumor suppressor gene. Bi‑allelic VHL alterations lead to inactivation of pVHL, which plays a major role by downstream activation of the hypoxia inducible factor (HIF) pathway. Somatic VHL mutations occur in 80% of sporadic ccRCC cases and the second most frequently mutated gene is polybromo 1 (PBRM1). As there is currently no data regarding PBRM1 involvement in VHL disease‑associated ccRCC, the aim of the present study was to assess the PBRM1 mutational status, and PBRM1 and HIF expression in VHL disease‑associated ccRCC series compared with a sporadic series. PBRM1 gene was screened by Sanger sequencing for 23 VHL‑disease‑associated ccRCC and 22 sporadic ccRCC cases. Immunohistochemical studies were performed to detect the expression of PBRM1, HIF1 and HIF2 for all cases. In VHL‑associated tumors, 13.0% (n=3/23) had PBRM1 somatic mutations and 17.4% (n=4/23) had a loss of PBRM1 nuclear expression. In sporadic cases, 27.3% (n=6/22) showed PBRM1 somatic mutations and 45.5% (n=10/22) had a loss of PBRM1 nuclear expression. Loss of PBRM1 was associated with an advanced tumor stage. HIF1‑positive tumors were observed more frequently in the VHL‑associated ccRCC than in the sporadic series. Furthermore, in the VHL cohort, PBRM1 expression appeared to be associated more with HIF1 than with HIF2. Given that hereditary tumors tend to be less aggressive, these results would suggest that co‑expression of PBRM1 and HIF1 may have a less oncogenic role in VHL‑associated ccRCC.

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