Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases.
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.
Department of Otorhinolaryngology, University of Brescia, Brescia, Italy.
Mario
M
Turri-Zanoni
Daniela
D
Medicina
Davide
D
Lombardi
Marco
M
Ungari
Piera
P
Balzarini
Cristina
C
Rossini
Wilma
W
Pellegrini
Paolo
P
Battaglia
Carlo
C
Capella
Paolo
P
Castelnuovo
Gabriele
G
Palmedo
Fabio
F
Facchetti
Heinz
H
Kutzner
Piero
P
Nicolai
William
W
Vermi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D019938:Cyclin D1 / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D020570:Genes, myb / Q000502:physiology; D019942:Genes, p16 / Q000502:physiology; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009297:Nasal Mucosa; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010255:Paranasal Sinus Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
D004268:DNA-Binding Proteins; C101743:RREB1 protein, human; D014157:Transcription Factors; D019938:Cyclin D1; D019009:Proto-Oncogene Proteins c-kit; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human