Submission Details

There is abundant evidence published associating the CDKN2A gene with melanoma-pancreatic cancer syndrome since the gene-disease relationship was first proposed by Hussussian et al. (1994). Multiple case level studies have been performed with melanoma patients that have variants in the CDKN2A gene. Over 200 families has been reported worldwide and many variants are founder variants. The CDKN2A gene produces two different proteins p14(ARF) and p16(INK4a) by alternative splicing. Both proteins function as inhibitors of cell cycle progression, but regulate cell cycle through the TP53 pathway and the RB1 pathway respectively. CDKN2A germline mutations that result in the disruption of one of each transcripts or both have all been reported in patients with melanoma. But the spectrum of disease is slightly different in patients' phenotypes and in the mouse models. The patients with disruption of p14 also can have nerve sheath tumors, which has been reported in a few studies. CDK4 that is inhibited by p16 is also associate with Melanoma, cutaneous malignant. Assessment of CDK4 binding and p16 subcellular localization can accurately and rapidly determine the functional significance of melanoma associated p16INK4a mutations. Multiple in vivo knock-out mouse models with CDKN2A deficiency have been established to show tumorigenesis of melanoma and other types of tumors. All of these types of evidence are consistent with a definitive relationship between the CDKN2A gene and melanoma-pancreatic cancer syndrome.