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. 2019 Oct 1;8(10):1577.
doi: 10.3390/jcm8101577.

BRAF Mutations and Dysregulation of the MAP Kinase Pathway Associated to Sinonasal Mucosal Melanomas

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Free PMC article

BRAF Mutations and Dysregulation of the MAP Kinase Pathway Associated to Sinonasal Mucosal Melanomas

Maria Colombino et al. J Clin Med. .
Free PMC article

Abstract

Sinonasal mucosal melanoma (SNM) is a rare and aggressive type of melanoma, and because of this, we currently have a limited understanding of its genetic and molecular constitution. The incidence among SNMs of somatic mutations in the genes involved in the main molecular pathways, which have been largely associated with cutaneous melanoma, is not yet fully understood. Through a next-generation sequencing (NGS) approach using a panel of 25 genes involved in melanoma pathogenesis customized by our group, we performed a mutation analysis in a cohort of 25 SNM patients. Results showed that pathogenic mutations were found in more than 60% of SNM cases at a somatic level, with strikingly 32% of them carrying deleterious mutations in the BRAF gene. The identified mutations mostly lack the typical UV signature associated with cutaneous melanomas and showed no significant association with any histopathological parameter. Oncogenic activation of the BRAF-depending pathway, which may induce immune tolerance into the tumour microenvironment (i.e., by increasing the VEGF production) was poorly associated with mutations in genes that have been related to diminished clinical benefit of the treatment with BRAF inhibitors. Screening for mutations in BRAF and other MAPK genes should be included in the routine diagnostic test for a better classification of SNM patients.

Keywords: BRAF gene; MAPK pathway; cancer pathogenesis; mutation screening; sinonasal mucosal melanoma.

Conflict of interest statement

Paolo A. Ascierto has/had consultant and advisory role for Bristol Myers Squibb, Incyte, Merck Sharp & Dohme, Roche-Genentech, Novartis, Amgen, Array, Merck-Serono, and Pierre Fabre. He received research fund from Bristol Myers Squibb, Roche-Genetech, and Array. Giuseppe Palmieri has/had advisory role for Incyte, Merck Sharp & Dohme, Novartis, and Pierre Fabre. All the remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Spectrum of non-synonymous single-nucleotide variations (ns-SNV) and polymorphic variants. The table summarises the distribution of the identified mutations per gene and patient. In blue, pathogenic mutations; in light blue, variant of unknown significance (VUS); in brown, single-nucleotide polymorphisms (present in >1% general population). Number in the square indicates the total amount of VUSs in that sample. The “x” symbol in blue squares indicates the coexistence of a pathogenic mutation and a VUS into the same sample. N, nasal cavity; P, paranasal sinuses; f, female; m, male. In italic, Sardinian patients; in bold, non-Sardinian patients.
Figure 2
Figure 2
Type of non-synonymous sequence variants per gene. The graph summarises the number of pathogenic mutations (light blue bars), variants of unknown significance (red bars), and single-nucleotide polymorphisms (green bars) found in each individual gene analysed. ns-SNV, non-synonymous single nucleotide variants. VUS, variant of unknown significance. Mutations are intended as pathogenic variants.
Figure 3
Figure 3
Mutation spectra in the analysed samples. (left) Pie chart shows the percentage distribution of nucleotide variations in the analysed genes. (right) Pie chart shows the percentage of transitions versus transversions mutations in the analysed genes.
Figure 4
Figure 4
Intracellular molecular alterations and their effects on tumour microenvironment immune activity. Activated MAPK pathway in melanoma cells triggering immune escape mechanisms. Arrow, activating regulation, interrupted line, negative regulation. RTK, receptor tyrosine kinase. IFN, interferon. IL, interleukin. MDSC, myeloid-derived suppressor cell. TAM, tumour-associated macrophage. T-reg, regulatory T cell. DC, dendritic cell.

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References

    1. Cossu A., Casula M., Cesaraccio R., Lissia A., Colombino M., Sini M.C., Budroni M., Tanda F., Paliogiannis P., Palmieri G. Epidemiology and genetic susceptibility of malignant melanoma in North Sardinia, Italy. Eur. J. Cancer Prev. 2017;26:263–267. doi: 10.1097/CEJ.0000000000000223. - DOI - PubMed
    1. Lipsker D., Engel F., Cribier B., Velten M., Hedelin G. Trends in melanoma epidemiology suggest three different types of melanoma. Br. J. Dermatol. 2007;157:338–343. doi: 10.1111/j.1365-2133.2007.08029.x. - DOI - PubMed
    1. Postow M.A., Hamid O., Carvajal R.D. Mucosal melanoma: Pathogenesis, clinical behavior, and management. Curr. Oncol. Rep. 2012;14:441–448. doi: 10.1007/s11912-012-0244-x. - DOI - PubMed
    1. Lund V.J., Howard D.J., Harding L., Wei W.I. Management options and survival in malignant melanoma of the sinonasal mucosa. Laryngoscope. 1999;109:208–211. doi: 10.1097/00005537-199902000-00007. - DOI - PubMed
    1. Mallone S., De Vries E., Guzzo M., Midena E., Verne J., Coebergh J.W., Marcos-Gragera R., Ardanaz E., Martinez R., Chirlaque M.D., et al. Descriptive epidemiology of malignant mucosal and uveal melanomas and adnexal skin carcinomas in Europe. Eur. J. Cancer. 2012;48:1167–1175. doi: 10.1016/j.ejca.2011.10.004. - DOI - PubMed
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