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Unformatted text preview: asminogen activator
urokinase plasminogen activator receptor
vascular epithelial growth factor
vertical growth phase
wildtype p53 activated fragment 1 (CDKN1A) Abstract
Cutaneous malignant melanoma is an aggressive tumor of melanocytes in the skin
with rapidly increasing incidence. Patients with advanced disease have a poor
prognosis since the tumor is usually resistant to current therapies. Therefore, the
development of novel strategies for preventing and treating melanoma is important.
To explore novel therapies we need to find appropriate targets and for that knowledge
about the biology of melanoma is important. There is growing evidence suggesting
that NRAS has an important role in tumorigenesis and tumor maintenance in
malignant melanoma and that the RAS-RAF-ERK signaling pathway is constitutively
activated through multiple mechanisms, one of which is activating mutations in NRAS
In an initial study, we investigated the occurrence of activating mutation in the NRAS
gene in a subset of patients with hereditary melanoma carrying germ line CDKN2A
alterations. From this study we found differences in the frequency of NRAS mutations
between hereditary and sporadic melanomas. Activating mutations in NRAS codon 61
were found in 95% (20/21) of primary hereditary melanomas but in only 10% (1/10)
of sporadic melanomas. We also detected multiple activating NRAS mutations in
tumor cells from different regions of individual primary hereditary melanomas.
Activating mutations that were detected in the primary melanomas of these patients
were also retained in their metastases. We also found that NRAS mutations are present
in potential precursor lesions (dysplastic nevi). We concluded that the high frequency
of NRAS codon 61 mutations detected in these hereditary melanomas may be the
result of a hypermutability phenotype associated with the hereditary predisposition for
melanoma development in patients with germline CDKN2A mutations.
The presence of a mutant NRAS oncogene in sporadic and familial melanomas implies
that the NRAS oncogene may be an important target for prevention and treatment of
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