Abstract
Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with BRAF and NRAS mutations. We show that in addition to being less frequent, BRAF and NRAS mutations are different in mucosal melanoma compared to cutaneous melanomas. Strikingly, the BRAF and NRAS mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified. We also show that the atypical BRAF and NRAS mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes.
Highlights
The majority of melanomas have a cutaneous origin, approximately 5% arise from the eye or mucosa
Many variants have been described in the context of mucosal melanoma, but besides KIT mutations, there is still no clear consensus on the most frequent driver mutations
We catalogued alterations of the neuroblastoma RAS viral oncogene homolog (NRAS) and BRAF genes in mucosal melanoma and showed that they represent a significant portion of mutations (20%) in these tumors
Summary
The majority of melanomas have a cutaneous origin, approximately 5% arise from the eye (ocular melanoma) or mucosa (mucosal melanoma). Primary mucosal melanomas are rare, they are associated with a significantly worse prognosis compared to other melanoma subtypes, with the lowest five-year survival rate [1,2]. This poor prognosis can be attributed to a delay in diagnosis of the disease due to a lack of symptoms during early stages of the disease and to its occurrence in occult anatomic locations that are generally not amenable to self-examination. V600E/K mutations are less common in mucosal melanoma, rendering them less amenable to BRAF/MEK inhibitor therapies. A better characterization of the molecular pathogenesis of mucosal melanoma could offer new hope for the development of more effective systemic therapies. We discovered that there is very limited data comparing the type of NRAS and BRAF mutations in mucosal and cutaneous melanomas. We were able to show that in addition to being less frequent, NRAF and BRAF mutations are different in mucosal melanoma compared to cutaneous melanomas, with mucosal melanoma mutations being strikingly closer to the type of mutations found in cancers such as lung cancers, raising fundamental questions about their etiology
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