Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010). ... Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010). For a discussion of genetic heterogeneity of cutaneous malignant melanoma, see CMM1 (155600).
The identification of the CDKN2A gene (600160) in melanoma cell lines by study of homozygous deletions for the 9p21 region (Kamb et al., 1994) and the identification of nonsense, missense, and frameshift mutations in those cell lines that ... The identification of the CDKN2A gene (600160) in melanoma cell lines by study of homozygous deletions for the 9p21 region (Kamb et al., 1994) and the identification of nonsense, missense, and frameshift mutations in those cell lines that had at least one CDKN2 allele present (Kamb et al., 1994) suggested that mutations in this gene may be the basis of familial malignant melanoma in many instances. The mutations in this tumor suppressor gene are involved in many other malignancies, rivaling the p53 gene (191170) in its catholicity. Weaver-Feldhaus et al. (1994) isolated genomic clones that span a large region in 9p21 surrounding the presumptive tumor suppressor gene(s) thought to be involved in susceptibility to melanoma and to influence progression of certain other tumors. A set of sequence tagged sites in this region were developed. By using these markers and others previously reported, the 9p21 region was studied by physical mapping in 84 melanoma cell lines. Homozygous deletions of the 9p21 region were found in 56% of melanoma tumors tested. A putative tumor suppressor gene was localized to a region of less than 40 kb that lies proximal (centromeric) to the IFNA gene cluster. The results were consistent with previous genetic studies of MLM that mapped the gene to the region between IFNA1 and D9S126. Puig et al. (1995) presented evidence suggesting the existence of several tumor suppressor genes on 9p that are involved in the predisposition to and/or progression of CMM and excluded p16 from involvement in the early development of some melanoma tumors. Miller and Mihm (2006) stated that 25 to 40% of melanoma-prone families have mutations in the CDKN2A gene. Kannengiesser et al. (2007) identified 2 founder mutations in the CDKN2A gene (600160.0017 and 600160.0018) among families in southeastern France with cutaneous malignant melanoma.
In affected members of 3 unrelated Italian families with autosomal dominant malignant melanoma, Binni et al. (2010) identified heterozygous mutations in exon 1B of the CDKN2A gene affecting the p14(ARF) isoform (see 600160.0020 and 600160.0021). These 3 families ... In affected members of 3 unrelated Italian families with autosomal dominant malignant melanoma, Binni et al. (2010) identified heterozygous mutations in exon 1B of the CDKN2A gene affecting the p14(ARF) isoform (see 600160.0020 and 600160.0021). These 3 families were from a large cohort of 81 Italian families with melanoma who were negative for CDKN2A mutations affecting the p16(INK4) isoform and mutations in the CDK4 (123829) gene. Mutations affecting exon 1B were not found in any of 58 sporadic cases. In a population-based study of 35 melanoma patients with CDKN2A mutations, including 22 from the U.K. and 13 from 3 cities in Australia, and their relatives, Cust et al. (2011) estimated that hazard ratios (HR) for melanoma in mutation carriers relative to the general population was 87 in the U.K. and 31 in Australia. However, cumulative risk estimates were not different: 16% of U.K. and 20% of Australian mutation carriers would be diagnosed with melanoma by age 50 years, and 45% and 52%, respectively, by age 80 years. Contrary to the strong association between UV radiation exposure and melanoma risk for the general population, CDKN2A mutation carriers appear to have the same cumulative risk of melanoma irrespective of the ambient UV irradiance of the region in which they live.