Such founder mutations have been described in a

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Unformatted text preview: utations have been described in a number of different populations. Families with mutations in CDKN2A that affect only p14ARF are much less common than mutations that affect p16INK4A with or without affecting p14ARF (7, 74). A recent study characterized a germ line deletion, including the entire INK4/ARF locus in a French melanoma-neural system tumor family and identified a new large antisense RNA (named ANRIL), whose expression co-clusters with ARF. The identification of this large antisense noncoding RNA could be important in cancer molecular genetics both in hereditary predisposition to melanoma and in somatic alteration of the p15/CDKN2B-p16/CDKN2A-p14/ARF cluster observed in a large proportion of cancers (75). Germline mutations of CDK4, an RB-kinase that is inhibited by INK4A, have also been identified in a small number of melanoma-prone kindreds in different populations (US, UK, Norway, France, Latvian, Australia). CDK4 is located on chromosome 12q14. So far, only seven kindreds carrying CDK4 germline mutations have been documented. Two US families carry an R24C mutation and the remaining carry R24H germ line CDK4 mutations (76). These mutations thus target a conserved arginine residue (R24) and render the mutant protein insensitive to inhibition by the INK4 class of cell cycle inhibitors. Thus, the CDK4 germline mutation identified, abolishes the binding of CDK4 to p16INK4A, providing further evidence that impaired p16-mediated cell cycle regulation may predispose carriers to melanoma development. Melanomas from patients harboring these germline CDK4 mutations do not demonstrate somatic INK4A inactivation, and inactivation of INK4A and CDK4 activation are thus mutually exclusive (77). Germ line mutations in CDKN2A and CDK4 genes, however, only account for minority of families with melanoma. Mutations in these genes are more frequent in families with many affected cases with CMM, and they are thus regarded as high risk genes. Variations in other genes have also been associated with increased risk of melanoma, particularly MC1R (the melanocortin 1 receptor gene). The MC1R gene,...
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This document was uploaded on 03/06/2014.

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