In our study, we investigated the prevalence and distribution of such genetic Ixazomib solubility alterations in MPM patients. A high prevalence of somatic mutations in BRAF gene was detected in incident and subsequent melanomas. The frequency of BRAF mutations Inhibitors,Modulators,Libraries in primary melanomas was Inhibitors,Modulators,Libraries consistent with that observed in our previous study on 451 Italian patients with single melanoma and slightly higher than that reported in a meta analysis on 2521 patients with cutaneous melanomas. In our series, two BRAFV600 mutation subtypes were detected V600E and V600K. Such two variants represent the most preva lent BRAF mutations and are able to constitutively activate BRAF Inhibitors,Modulators,Libraries kinase. Amplification of CyclinD1 and cKIT genes, as determined by FISH analysis, was found in about 14% and 5% of melanoma tis sues from our series, respectively.

Again, such frequencies were consistent with those reported in literature. One out of 229 melanoma samples presented a coexistence of BRAF mutation and cKIT amplification, confirming Inhibitors,Modulators,Libraries that aberrations in these two genes can be considered as mutually exclusive. A markedly higher rate of either BRAF mutations or CyclinD1 or cKIT amplifications was previously observed in 32 melanoma cell lines as controls by our group. As reported, these control cell lines were established as primary cell cultures from tumor samples obtained from donor patients with documented diagnosis of melanoma. Since cultured melanomas are thought to represent cells with the most malignant phenotype, one could speculate that genetic alterations in these three candidate genes play a role in tumor progression.

Sixty two paired samples from 54 patients showed discrepancies in BRAFcKITCyclinD1 mutation patterns between first and subsequent primary melano mas. In the discrepant cases, we observed 20 patients with a wild type first tumor and a mutated subsequent tumor, 14 with a mutated first tumor and a wild type subsequent tumor, 8 with Inhibitors,Modulators,Libraries change in alteration variants between the two tumor lesions, and 12 with an additional gene amplifica tion in the two BRAF mutated tumors. In majority of cases, gene alterations seem to be acquired in subsequent melanomas. Moreover, while BRAF mutations were equally distributed among discrepant multiple melanomas, rates of cKIT and CyclinD1 amplification were found to signifi cantly increase moving from incident to subsequent primary melanomas. Such discrepancies were also confirmed among paired primary melanomas located at the same anatomical promotion site as well as in synchronous primary melanomas.