title: Loss of PBRM1 expression is associated with renal cell carcinoma progression.
abstract: 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.
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawłowski
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Mühl
authors.forename: Tullio
authors.initials: T
authors.lastname: Sulser
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Peter
authors.initials: P
authors.lastname: Schraml
mesh_terms: D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D018450:Disease Progression; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009154:Mutation; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human