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Unformatted text preview: e defined for oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12) (64). Gain of chromosome 7q is common in CMM suggesting that BRAF, located on 7q34, is a target for gene amplification (65). Moreover, cyclin D1, a down-stream target of the MAPK pathway and a p16INK4A antagonist, is amplified in acral lentigiuous CMM in which BRAF and NRAS mutations are infrequent. Frequent findings of homozygous deletions of the 9p21 locus confirmed the importance of the INK4 gene locus(66). Homozygous deletions on 10q23 where PTEN gene is located are also frequent in melanoma (67). Susceptibility genes in melanoma Two genes conferring susceptibility to melanoma have been identified within highrisk families, CDKN2A and CDK4. Both of these genes are important in controlling cell division. As stated above, CDKN2A codes for two proteins, p16IKN4A, a tumor suppressor, which has a key role in the CDK4–cyclin D–retinoblastoma protein (RB) pathway and in the regulation of the G1 checkpoint of the cell cycle and p14ARF, important in the p53 pathway (Figure 5). Germline CDKN2A mutations occur in many patients with a hereditary predisposition to melanoma (68-71). Overall, approximately half of all melanoma-prone families, the disease shows genetic linkage to 9p21, the chromosome arm where the CDKN2A gene is located, and approximately 40% of these families carry germline mutations in CDKN2A. In Sweden, a CDKN2A mutation consisting of a 3-base-pair (bp) insertion leading to an extra arginine residue in codon 113 in exon 2 (113insR) has been identified in several Swedish families (68, 69). Aitken et al. in 1999 found mutations 18 of CDKN2A in 10.3% of a population of high-risk families from Australia. They estimated that 0.2% of melanoma in Australia was due to mutations in CDKN2A(72). Many of the recurrent mutations in p16INK4A that have been described are founder mutations dating back up to 100 generations, including the 113insR a Swedish founder mutation (73). Such founder m...
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This document was uploaded on 03/06/2014.

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