Activating nras mutations have been correlated with

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Unformatted text preview: have been correlated with the nodular melanoma subtype and with sun exposure (37-40). The presence of NRAS mutations in tumor associated nevi and RGP lesions suggests that NRAS activation occurs at an early stage during melanoma development (35, 36). RAF: The RAF family of serine-threonine kinases function downstream of RAS in signal transduction. The most commonly mutated component of RAS-RAF-ERK pathway in melanoma is BRAF. BRAF is mutated in 50 % - 70% of melanomas and the most common mutation is a glutamic acid for valine substitution at position 600 14 (V600E) (36, 41). About 80% of benign nevi carry this mutation as well, but so far no mutations have been detected in uveal melanomas (42). The BRAF gene resides at chromosome 7q34, a chromosomal region that is frequently amplified in melanoma tumors (43). PI3K: Mutations of PIK3CA (encoding the p110 alpha catalytic subunit of PI3K) are rarely detected in melanoma, and are found in less than 1% of primary melanomas and 3% of melanoma metastases, with no evidence of amplification of any PI3K subunit in primary melanomas by array CGH (44, 45). AKT: Constitutive activation of AKT has been shown to be a potent oncogenic lesion for melanocyte transformation (46). AKT3 is the major isoform deregulated in melanoma. DNA copy gains involving the AKT3 locus have been described in melanoma, and selective AKT3 activation may characterize 40%–60% of sporadic tumors (47). Recent data have suggested that activation of different AKT isotypes may result in distinct effects on cell proliferation and survival. For example, among the three AKT isotypes, AKT3 was correlated most strongly with melanoma tumor progression, and targeted AKT3 depletion triggered apoptotic signaling (47). PTEN: PTEN is another important element in signal transduction altered in human melanomas. PTEN was identified as a tumor suppressor candidate from the chromosome region 10q23-24 which is frequently deleted in gliomas and melanomas (48, 49). Cytogenetic evidence show...
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