CDK4 and osteosarcoma: Notably, in addition to RB1 loss of function events, RB1 signaling is also perturbed by commonly described point mutations and amplification or loss of upstream pathway regulators such as CDKN2A, CDKN2B, CDKN2C, CDK4, CDK6, CCD2. Loss of CDKN2A in 45Ca murine models and methylation of CDKN2A in a human osteosarcoma model was not associated with increased ciliogenesis or Hh response.