Abstract
PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC.
Highlights
The estimated new kidney cancer cases diagnosed in the world and the United Sates every year are ~300,000 and ~63,000, respectively (Global Burden of Disease Cancer et al, 2015; Siegel et al, 2016)
Von Hippel-Lindau (VHL) is the substrate recognition of an E3 ligase that labels Hypoxia-inducible factor (HIF) 1α and 2α with ubiquitin for degradation (Kaelin, 2007; Majmundar et al, 2010; Masson and Ratcliffe, 2014; Semenza, 2013)
We identified HIF1 and STAT3 motifs from differentially expressed genes to determine the strength of regulation of the targets by individual transcription factor binding motifs (TFBMs)
Summary
The estimated new kidney cancer cases diagnosed in the world and the United Sates every year are ~300,000 and ~63,000, respectively (Global Burden of Disease Cancer et al, 2015; Siegel et al, 2016). Clear cell renal cell carcinoma (ccRCC) is the most common subtype (75%) and is lethal when metastasized (Rini et al, 2009). The Von Hippel-Lindau (VHL) tumor suppressor gene is the most frequently mutated gene in ccRCC (Gnarra et al, 1994; Linehan et al, 1995), and its complete loss constitutes an early, truncal oncogenic driver event. Human ccRCC is highly vascular due to uncontrolled activation of HIFα targets that regulate angiogenesis. Thereby, anti-VEGF/ VEGFR agents are effective, first-line treatment for metastatic ccRCC (mRCC) (Rini et al, 2009; Voss et al, 2013)
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