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Unformatted text preview: mors with
mutations and 53% of tumors with multiple copies of KIT demonstrated increased
KIT protein levels (57).
p16INK4A : Sporadic and familial melanomas have been associated with mutations,
loss of heterozygosity, and deletions in the CDKN2A locus, which is important for
the normal progression of the cell cycle. Somatic inactivation of CDKN2A (p16INK4A
and p14ARF) is frequently detected in melanoma cell lines but less commonly in
primary tumors (58). Biallelic CDKN2A deletions however, have been reported in
about 45% of CMM metastases and associated with adverse prognosis, emphasizing
the importance of this locus in disease progression (59).
Expression of p16INK4A has been reported to correlate inversely with aggressive
melanoma behavior; nevertheless, mutations at this locus also have been detected in
normal melanocytes and in benign compound nevi lacking signs of clinical or
histologic atypia (27).
p53 and p14ARF: Mutations in TP53 (the p53 gene) are the most common
contributors to the etiology of neoplastic disorders, but their role in the pathogenesis
16 of melanoma has not been established. TP53 mutations are in infrequent in primary
human melanoma, thus, there is no apparent correlation between TP53 gene
rearrangements or altered expression of the p53 protein and progression of
melanocytic lesions. Nevertheless, some authors suggest that p53 could have a more
complex role in the pathogenesis of melanoma by acting on downstream effector
genes, such as HDM2, GADD45, and CIP1/WAF1 (27). ARF has been thought to
function predominantly as a positive regulator of the p53 tumor suppressor through
inhibition of HDM2. Loss of ARF could thus explain the lack of TP53 mutations in
melanomas. However, experimental evidence has recently showed, that ARF
functions as a tumor suppressor by inducing p53-independent senescence.
Accordingly, ARF– and p53- deficient mice do not exhibit identical tumor
phenotypes, and ARF interacts with a variety of other proteins, including E2F1, Myc,
NF-κB, and can function independently of p53 in ribosome biosynthesis, DNA
damage response, apoptosis, and autophagy (60). Chromosomal abnormalit...
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