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Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway
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 induc...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548775/ https://www.ncbi.nlm.nih.gov/pubmed/34712359 http://dx.doi.org/10.3892/ol.2021.13096 |
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author | 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 |
author_facet | 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 |
author_sort | Gad, Sophie |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8548775 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-85487752021-10-27 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 Oncol Lett Articles 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. D.A. Spandidos 2021-12 2021-10-15 /pmc/articles/PMC8548775/ /pubmed/34712359 http://dx.doi.org/10.3892/ol.2021.13096 Text en Copyright: © Gad et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles 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 Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway |
title | Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway |
title_full | Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway |
title_fullStr | Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway |
title_full_unstemmed | Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway |
title_short | Involvement of PBRM1 in VHL disease-associated clear cell renal cell carcinoma and its putative relationship with the HIF pathway |
title_sort | involvement of pbrm1 in vhl disease-associated clear cell renal cell carcinoma and its putative relationship with the hif pathway |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548775/ https://www.ncbi.nlm.nih.gov/pubmed/34712359 http://dx.doi.org/10.3892/ol.2021.13096 |
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