Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases

• Published in: Head & neck Vol. 35; no. 8; pp. 1066 - 1077
• Main Authors: Turri-Zanoni, Mario, Medicina, Daniela, Lombardi, Davide, Ungari, Marco, Balzarini, Piera, Rossini, Cristina, Pellegrini, Wilma, Battaglia, Paolo, Capella, Carlo, Castelnuovo, Paolo, Palmedo, Gabriele, Facchetti, Fabio, Kutzner, Heinz, Nicolai, Piero, Vermi, William
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2013; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Cohort Studies; Cyclin D1 - physiology; DNA-Binding Proteins - physiology; Female; Genes, myb - physiology; Genes, p16 - physiology; Genes, ras - physiology; Humans; Kinases; Male; Melanoma; Melanoma - genetics; Melanoma - pathology; Melanoma - therapy; Middle Aged; Mutation; Mutation - physiology; Nasal Mucosa; NRAS; Paranasal Sinus Neoplasms - genetics; Paranasal Sinus Neoplasms - pathology; Paranasal Sinus Neoplasms - therapy; PI3K/Akt pathway; Proto-Oncogene Proteins B-raf - physiology; Proto-Oncogene Proteins c-kit - physiology; PTEN Phosphohydrolase - physiology; RAS-MAPK pathway; sinonasal melanoma; Transcription Factors - physiology; NRAS; RAS-MAPK pathway; PI3K/Akt pathway; KIT; sinonasal melanoma
• ISSN: 1043-3074; 1097-0347
• DOI: 10.1002/hed.23079

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. Head Neck, 2013