Although BRAF and NRAS mutations are likely to be important for the initiation and maintenance of some melanomas, other factors might be more significant for proliferation and prognosis in subgroups of aggressive melanoma.
This finding further underlines the distinction between uveal and cutaneous melanomas, and suggests that BRAF inhibitors are unlikely to benefit patients with uveal melanoma.
Because of the very sensitive PAP technology, B-RAF mutations were found in cell lines and primary uveal melanomas, which suggests that they may occasionally play a role in the activation of the MAPK pathway in uveal melanoma and indicates a higher prevalence of B-RAF mutations in uveal melanoma than was reported earlier.
BRAF mutations, including tandem mutations, were frequently found in both thin and thick primary melanomas, implying that these mutations can occur early in the progression of melanoma.
Tumors with BRAF mutations were also significantly more likely to occur in association with a contiguous nevus (odds ratio 3.49, 95% confidence interval 1.06-11.46), although a contiguous nevus was not found in all melanomas with a BRAF mutation.
Inhibition of (V600E)B-Raf or Akt3 in advanced melanoma cells in which both pathways were active reduced anchorage-independent growth and tumor development in a cooperatively acting manner.
In summary, this report indicates that N-RAS(Q61K) and B-RAF(V600E) contribute to melanoma's resistance to apoptosis in part by downregulating Bim expression, suggesting that Bim is a possible treatment target for overriding melanoma's inherent defenses against cell death.
These data suggest that SPRY2, an inhibitor of ERK signaling, may be bypassed in melanoma cells either by down-regulation of its expression in WT BRAF cells, or by the presence of the BRAF mutation.
The BRAF mutation was observed frequently even in small lesions, indicating that activation of this gene may be one of the early events in the pathogenesis of some melanomas.
Mutant B-RAF is frequently expressed in melanoma and overrides growth factor and matrix adhesion control of cyclin D1 and p27(Kip1) levels in human melanocytes.
Our results suggest that although nevus propensity is important for the occurrence of both BRAF and NRAS-mutant melanomas, ambient UV irradiance influences risk differently based on the age of exposure.
In conclusion, the T1799A BRAF mutation is present in a proportion of posterior uveal melanomas but within these tumours the distribution of the mutation is heterogeneous.
As BRAF and its effectors could be good melanoma therapy targets, defining the repertoire of genes that are differentially regulated because of BRAF mutational activation is an important objective.