CDK4 was the second high risk melanoma susceptibility gene identified . CDK4 is an oncogene located within the 12q14 chromosomal region and encodes a protein that controls cell cycle progression through the G1 phase. To date mutations in this gene have been described in 17 melanoma-prone families and in all of them the mutation affects the same amino acid (Arginine 24): p.Arg24Cys and p.Arg24His (Potrony M, et al. 2015. PMID: 26488006). These R24C and R24H mutations lead to CDK4 behaving as a dominant oncoprotein through loss of binding to p16, its negative regulator. Thus, when CDK4 is mutated, p16INK4A cannot inhibit the CDK4 kinase activity resulting in the progression of the cell cycle. In an analysis of 17 families, median age at first melanoma diagnosis was 39 years, and the lifetime mutation penetrance based on the available data was estimated at 74%(Read J, et al. 2016.PMID: 26337759). Phenotypically, individuals with CDK4 mutations cannot be distinguished from those with CDKN2A mutations . Both mutations are characterized by numerous atypical nevi and multiple primary melanomas.(Lee KC, et al. 2015. PMID:30190834).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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