MDM4 and nonpapillary renal cell carcinoma: While the exact combination of triple VHL, TP53, and RB1 mutations do not arise in human ccRCC, this model nonetheless reflects the frequent mutational inactivation of VHL combined with genetic dysregulation of cell cycle networks that commonly arise in human ccRCC involving multiple combinations of TP53 mutation or copy loss, MDM2 and MDM4 mutation or copy gain, copy losses of CDKN1 and CDKN2 family genes, copy losses of RB family genes, and copy gains of CYCLIN family genes and CDK family genes [14].