Dataset Information

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

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.

SUBMITTER: Colombino M

PROVIDER: S-EPMC6832198 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Colombino Maria M Paliogiannis Panagiotis P Cossu Antonio A De Re Valli V Miolo Gianmaria G Botti Gerardo G Scognamiglio Giosuè G Ascierto Paolo Antonio PA Santeufemia Davide Adriano DA Fraggetta Filippo F Manca Antonella A Sini Maria Cristina MC Casula Milena M Palomba Grazia G Pisano Marina M Doneddu Valentina V Lissia Amelia A Fedeli Maria Antonietta MA Palmieri Giuseppe G

Journal of clinical medicine 20191001 10

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 ...[more]

PMID: 31581559

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Project description:BackgroundPrimary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment.MethodsForty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry.ResultsMutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002).ConclusionsThese findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.

Dataset Information

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

Publications

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

Similar Datasets

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