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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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