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Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases
Mario Turri-Zanoni1, Daniela Medicina, Davide Lombardi
1Department of Otorhinolaryngology, University of Brescia, Brescia, Italy.
Background:
Primary sinonasal mucosal melanomas are aggressive tumors with a poor clinical control by current treatments, raising the urgent need of novel strategies.
Methods:
By fluorescence in situ hybridization (FISH), direct sequencing, and immunohistochemistry, we investigate the spectrum of molecular abnormalities in a cohort of 32 cases of primary sinonasal mucosal melanomas.
Results:
We found that all primary sinonasal mucosal melanomas lack BRAF V600E mutation; in addition, they are characterized by somatic mutations of NRAS (22%) and KIT (12.5%), together with amplification of RREB1 (100%) and loss of MYB (76%). The large majority of cases showed KIT protein expression (96.9%). Among tumor suppressor genes, primary sinonasal mucosal melanomas showed loss of PTEN (48.1%) and p16/INK4a (55.2%). All tested cases showed expression of pAkt and pErk, suggesting a combined activation of PI3K/Akt and RAS-mitogen-activated protein kinase (MAPK) pathways.
Conclusions:
This molecular fingerprint strongly argues against the clinical efficacy of BRAF-inhibitors, but could candidate primary sinonasal mucosal melanomas to therapeutic strategies targeting RAS and KIT mutations or inhibiting PI3K-Akt-mTOR pathway.
Insights
Primary sinonasal mucosal melanomas lack BRAF V600E mutations, indicating BRAF-inhibitors are ineffective. Instead, targeting RAS and KIT mutations or the PI3K-Akt-mTOR pathway may offer new therapeutic strategies for these aggressive tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Primary sinonasal mucosal melanomas are aggressive cancers.
- Current treatments offer poor clinical control.
- Novel therapeutic strategies are urgently needed.
Purpose of the Study:
- To investigate the molecular abnormalities in primary sinonasal mucosal melanomas.
- To identify potential therapeutic targets.
Main Methods:
- Fluorescence in situ hybridization (FISH)
- Direct sequencing
- Immunohistochemistry
- Analysis of 32 primary sinonasal mucosal melanoma cases.
Main Results:
- Absence of BRAF V600E mutation in all cases.
- Somatic mutations in NRAS (22%) and KIT (12.5%).
- Amplification of RREB1 (100%) and loss of MYB (76%).
- Loss of tumor suppressor genes PTEN (48.1%) and p16/INK4a (55.2%).
- Activation of PI3K/Akt and RAS-MAPK pathways indicated by pAkt and pErk expression.
Conclusions:
- BRAF-inhibitors are unlikely to be effective.
- Therapeutic strategies targeting RAS and KIT mutations are promising.
- Inhibiting the PI3K-Akt-mTOR pathway could be beneficial.
