Inactivation of VHL due to mutation or DNA methylation is an early event in ccRCC that leads to accumulation of the transcription factor HIF-α, which dimerizes with HIF-β and translocates to the nucleus. The resulting HIF-α–HIF-β-induced upregulation of downstream genes promotes cell proliferation, glucose uptake, glycolysis, and angiogenesis.
Mutations in chromatin remodellers and histone modifiers including PBRM1, SETD2, BAP1 and KDM5C lead to global abnormal gene expression patterns, and deficiency in DNA repair, which contributes to genomic instability.
Activation of PI3K–mTOR signalling promotes cell proliferation and tumour aggression, and increases translation of HIF-α, leading to enhanced HIF-α-mediated gene expression. The proposed development pattern of ccRCC is based on tumour evolution analyses and current understanding of genomic variation.
Description adapted from "Precision medicine from the renal cancer genome", Riazalhosseini and Lathrop.
Additional sources of information:
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