Abstract
Clear cell renal carcinoma is the most common form of kidney cancer, which is one of the ten leading causes of cancer death in the United States. The initial genetic event in most clear cell renal carcinomas is inactivation of the VHL tumor suppressor gene. Subsequent cooperating genetic events include gain of chromosome 5q, loss of chromosome 14q, and intragenic mutations affecting various chromatin modifiers, such as PBRM1 and BAP1, and genes linked to the mTOR pathway. The VHL gene product, pVHL, is the substrate recognition component of an ubiquitin ligase complex that targets the alpha subunit of the HIF transcription factor for polyubiquitylation and proteasomal degradation. Deregulation of HIF, and particularly HIF2, appears to play an important role in pVHL-defective clear cell renal carcinomas. HIF controls many genes that promote adaptation to hypoxia, including VEGF. This likely explains the highly angiogenic nature of clear cell renal carcinoma and its sensitivity to VEGF inhibitors. This chapter will review the molecular pathogenesis of clear cell renal carcinoma and potential therapeutic targets.
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Kaelin, W.G. (2015). Molecular Biology of Kidney Cancer. In: Lara, P., Jonasch, E. (eds) Kidney Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-17903-2_3
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