Loss of PBRM1 expression is associated with renal cell carcinoma progression

• Published in: International journal of cancer 2013-01, Vol.132 (2), p.E11-E17
• Main Authors: Pawłowski, Rafal, Mühl, Sarah M., Sulser, Tullio, Krek, Wilhelm, Moch, Holger, Schraml, Peter
• Format: Article
• Language: English
• Subjects: BAF180; Cancer; Cancer therapies; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Disease Progression; Gene Expression; Humans; Kaplan-Meier Estimate; Kidney cancer; Kidney Neoplasms - metabolism; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Medical research; Mutation; Neoplasm Staging; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; PBRM1; renal cell cancer; Tissue Array Analysis; Transcription Factors - genetics; Transcription Factors - metabolism; Tumors; VHL; Von Hippel-Lindau Tumor Suppressor Protein - genetics
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27822

Although von Hippel‐Lindau (VHL) tumor suppressor gene alterations dominate the genetic landscape of clear cell renal cell carcinoma (ccRCC), recent studies have identified new ccRCC genes, including SETD2, KDM6A, KDM5C, BAP1 and PBRM1. Strikingly, all these genes fall into a category of histone/chromatin regulators. Polybromo‐1 (PBRM1) is the second most frequently mutated gene after VHL; however, the clinical relevance of its loss in ccRCC has not yet been reported. Here, we analyzed the expression of PBRM1, the product encoded by PBRM1, in ccRCC cell lines and in more than 300 RCC tumor samples. The data were correlated with clinicopathological parameters and VHL mutation status. We found that a significant number of ccRCC cancer cell lines lack detectable PBRM1 expression. Loss of PBRM1 was predominant in the clear cell subtype of RCC (∼ 70%) and correlated with advanced tumor stage (p < 0.0001), low differentiation grade (p = 0.0002) and worse patient outcome (p = 0.025), but not with the VHL mutation status. Our results indicate a critical role for PBRM1 in the suppression of ccRCC progression. Moreover, the results suggest that functional inactivation of PBRM1 in the context of pVHL loss‐of‐function may represent a key event in facilitating the development of key aspects of an aggressive tumor behavior. Given the role of PBRM1 in chromatin modification, the gene expression pathways disrupted by the inactivation of this protein may lead to new treatment strategies for ccRCC. What's new? The gene coding for polybromo‐1 (PBRM1) is known to have the second‐highest mutation frequency in clear cell renal cell carcinoma (ccRCC) tumors, but the clinical and prognostic relevance of these mutations has been uncertain. Using tissue microarrays, the authors found that loss of PBRM1 function is correlated with advanced tumor stage, poor differentiation, and worse patient outcome. These results suggest that PBRM1 is crucial for the suppression of aggressive ccRCC tumors. Given its role in chromatin modification, pathways that are regulated by PBRM1 may also provide new therapeutic targets for ccRCC.