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Loss of PBRM1 expression is associated with renal cell carcinoma progression
Author(s) -
Pawłowski Rafal,
Mühl Sarah M.,
Sulser Tullio,
Krek Wilhelm,
Moch Holger,
Schraml Peter
Publication year - 2012
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.27822
Subject(s) - bap1 , clear cell renal cell carcinoma , cancer research , biology , context (archaeology) , histone , chromatin remodeling , tumor suppressor gene , gene , mutation , renal cell carcinoma , medicine , oncology , genetics , carcinogenesis , melanoma , paleontology
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.