Lack of cytoplasmic ERK activation is an independent adverse prognostic factor in primary cutaneous melanoma.

The aim of this study was to estimate the impact on survival of NRAS and BRAF mutations and activation of Akt and extracellular signal-regulated kinase (ERK) in primary melanomas. A cohort of 57 primary cutaneous T1-2 melanoma tumors was analyzed. Mutation frequency for both genes was 61% (NRAS 26% and BRAF 39%). In a univariate analysis, shorter overall survival was associated with the presence of ulceration (P=0.001) and BRAF exon 15 mutations (P=0.005) as well as the absence of nuclear activation of Akt (P=0.022) and of cytoplasmic activation of ERK (P=0.003). Unexpectedly, ulceration was a significant adverse prognostic factor only in melanomas with BRAF mutations, whereas there was no effect of ulceration on overall survival in tumors with wild-type BRAF. A multivariate analysis showed that significant independent adverse survival prognostic markers were absence of cytoplasmic activation of ERK (P=0.007) and ulceration (P=0.008), whereas BRAF exon 15 mutation status showed a nonsignificant trend (P=0.066). The absence of cytoplasmic ERK activation in poor prognosis T1-2 melanomas may be associated with activation of some other uncharacterized pathway leading to tumor progression and adverse outcome. Immunohistochemical analysis of cytoplasmic phosphorylated ERK could be used as a prognostic marker in primary melanomas if confirmed in another data set.

Mutations of PIK3CA are rare in cutaneous melanoma.

Recent studies have shown that the PIK3CA gene, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinases, is mutated in human cancers. To determine whether PIK3CA is altered in cutaneous melanoma, we screened a series of 101 melanoma metastases. We identified PIK3CA missense mutations in three metastases (3%). Interestingly, these mutations were observed only in tumours that were negative for NRAS mutations. Using immunohistochemistry, we also analysed our metastases for the expression of phosphorylated Akt. These analyses revealed a moderate to strong phosphorylated Akt expression in 78% (21 of 27) of metastases with NRAS mutations and in 73% (54 of 74) of metastases without NRAS mutations. Interestingly, the three metastases with mutations in PIK3CA all exhibited a strong expression of phosphorylated Akt. Taken together, our results show that PIK3CA is mutated in a minority of melanomas and suggest that mutations in this gene may represent an alternative mechanism of Akt activation in cutaneous melanoma.