Identification of mutations of the SWI/SNF complex gene PBRM1 by exome sequencing in renal carcinoma.

Teh, Bin Tean; Varela, Ignacio; Tarpey, Patrick; Huang, Dongzhou; Ong, Choon Kiat; Furge, Kyle A.; Campbell, P.J.; Stratton, M. R.; Futreal, P. Andy

doi:10.1200/jco.2011.29.15_suppl.4571

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“…Mutations in the Polybromo-1 ( PBRM1 ) gene, also known as BRG1-associated factor 180 (BAF180), a component of the SWI/SNF-B (PBAF) chromatin-remodeling complex, are observed in roughly 50% of ccRCC (11, 12). BRCA1 associated protein-1 ( BAP1 ), a deubiquitinating enzyme of the ubiquitin carboxyl-terminal hydrolase (UCH) family, and Set domain-containing 2 ( SETD2 ), a histone methyltransferase that is specific for lysine 36 of histone H3, are found to be mutated in ~10 to 15% of ccRCC (13–15).…”

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confidence: 99%

Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade

et al. 2017

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Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutation, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with Pax8, a developmental lineage-specific transcription factor, led to ccRCC of different grade. Bap1-deficient tumors were high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histological grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCC may arise from Bowman capsule cells.

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