Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS

Abstract

In contrast to cutaneous melanoma, there is no evidence that BRAF mutations are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in uveal melanoma, although there is increasing evidence that this pathway is activated frequently in the latter tumours. In this study, we performed mutation analysis of the RAS and BRAF genes in a panel of 11 uveal melanoma cell lines and 19 primary uveal melanoma tumours. In addition, Western blot and immunohistochemical analyses were performed on downstream members of the MAPK pathway in order to assess the contribution of each of these components. No mutations were found in any of the three RAS gene family members and only one cell line carried a BRAF mutation (V599E). Despite this, mitogenactivated protein kinase/extracellular signal-regulated kinase kinase (MEK), ERK and ELK were constitutively activated in all samples. These data suggest that activation of the MAPK pathway is commonly involved in the development of uveal melanoma, but occurs through a mechanism different to that of cutaneous melanoma.

Molecular pathology of uveal melanoma

“…91 Most UM demonstrate constitutive activation of the MAPK pathway, suggesting the presence of upstream activating mutations. 11,22,23 However, a systematic interrogation of candidate oncogenes in the MAPK pathway undertaken by several groups was initially disappointing. 24 For example, mutations in KIT and the three RAS family members, which can activate the MAPK pathway, were shown to be exceedingly rare in UM.…”

“…Self-sufficiency in growth signals Gain of cell cycle stimulator-activation of pathways The PI3K-AKT prosurvival pathway is constitutively activated in UM. LOH of the PTEN locus occurs in 76% of UM [17][18][19][20][21] The RAF/MEK/ERK pathway is constitutively activated: activating mutations in GNAQ or GNA11 occur in 480% of UM and can activate the RAF/ MEK/ERK pathway 11,[22][23][24][25][26][27][28] …”

“…24 For example, mutations in KIT and the three RAS family members, which can activate the MAPK pathway, were shown to be exceedingly rare in UM. 23,[63][64][65][66]92 Similarly, BRAF mutations, well described in cutaneous melanomas, have been reported in choroidal melanomas, 67 but are very rare. 22,23,65,68,93 Further, mutations in the other two members of the RAF family, ARAF and CRAF, are not found in UM.…”

“…23,[63][64][65][66]92 Similarly, BRAF mutations, well described in cutaneous melanomas, have been reported in choroidal melanomas, 67 but are very rare. 22,23,65,68,93 Further, mutations in the other two members of the RAF family, ARAF and CRAF, are not found in UM. 24 Guanine nucleotide-binding protein G(q) subunit (GNAQ, or G-alpha-q) and GNA11 mutations This puzzle concerning the MAPK pathway, and the mechanisms by which it was constitutively activated, persisted until the recent discovery of mutations in GNAQ in almost half of UM.…”

Inflammation in uveal melanoma

“…For instance, in cutaneous melanoma, BRAF gene mutations are initiators of malignancy, whereas in uveal melanoma, this role is played by mutations in the GNAQ and GNA11 genes. [5][6][7][8][9] Such mutations activate biochemical pathways that induce cell division.…”