NRAS and melanoma: It is likely that secondary events are necessary for metastatic progression in addition to mutations in either BRAF or NRAS, but this could occur through alteration of other tumor suppressor genes or oncogenes not investigated here, such as CDK4, PTEN, and TP53, as well as CDKN2A. As only melanomas with wild-type BRAF have amplified CDK4 and cyclin D1 genes, the CDKN2A-CDK4/6-cyclin D pathway is viewed as linearly downstream of BRAF (Zhao et al.,2008).