SF3B1, NRAS, KIT, and BRAF Mutation; CD117 and cMYC Expression; and Tumoral Pigmentation in Sinonasal Melanomas

Abstract

Sinonasal melanomas encompass melanoma arising in the nasal cavity and paranasal sinuses. Despite recent advances in tumor genomics, correlation between mutational status and protein expression with prognosis and tumor pigmentation has not been carried out in sinonasal melanomas. Ninety-five sinonasal melanomas from 95 patients were included. As per univariate analyses, age was the only variable that significantly correlated with progression-free survival. SF3B1, NRAS, KIT, and BRAF mutations were documented in 7% (5/72), 22% (16/72), 22% (16/72), and 8% (6/72) of cases, respectively. Comutation was detected in 6 cases: NRAS and KIT in 2 cases; NRAS and BRAF in 2 cases; SF3B1, KIT, and BRAF in one case; and SF3B1, NRAS, and KIT in one case. Correlations approaching statistical significance were observed between BRAF mutation status and poorer overall survival and progression-free survival (log-rank P-values=0.054 and 0.061). Increased CD117 expression (33%, 29/88) and decreased nuclear cMYC expression (40%, 39/84) significantly correlated with cytoplasmic pigmentation. Several SF3B1, NRAS, and KIT mutations not previously documented in sinonasal melanomas were detected in our series, suggesting a potential role for targeted therapies. A similar frequency of SF3B1, NRAS, and KIT mutations was noted in Asian cases, whereas NRAS, KIT, and BRAF mutations were predominant in the United States and European cases; however, the number of included cases was small. The significant association between CD117 and cMYC expression with increased cytoplasmic pigmentation in our series suggests that the pigmented morphologic appearance of sinonasal melanomas could be attributed to the underlying oncogenic mutations and metabolic interaction.

Morpho-Molecular Assessment Indicates New Prognostic Aspects and Personalized Therapeutic Options in Sinonasal Melanoma

“…Our cohort had one patient with a canonical –124C>T mutation and one patient with a –185C>G mutation, which was previously unknown. SF3B1 mutations, reported at low frequencies in other cohorts [11], were not present in our cohort. A study from Cosgarea et al investigate mucosal melanomas using a NGS panel including 15 head and neck primary tumors.…”

“…Another group looks at 29 genes and finds alterations in mainly NRAS or KRAS , but no KIT mutation [10]. The most recent study analyzes a large cohort of 95 sinonasal melanomas [11]. However, only BRAF , NRAS , KIT and SF3B1 are investigated by Sanger sequencing.…”

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

“…Exon 15 BRAF V600E variant was most frequent in cutaneous melanoma with a UV signature [39,40,41]. Recently, some studies reported the prevalence of BRAF mutations as lower than 10% in SNM patients [24,42,43]. In the present study, data revealed that SNM lack the mutational signature of UV light, predominantly of transversion mutation, in overall genes tested, thus unveiling a different mutational signature between cutaneous and SNM subtypes.…”

Prognostic Roles of BRAF, KIT, NRAS, IGF2R and SF3B1 Mutations in Mucosal Melanomas

“…In a large series of 706 mucosal melanomas, KIT and BRAF mutational status did not correlate with overall survival (OS); however, NRAS was not analyzed in this series [6]. Correlation between NRAS, BRAF and KIT mutations and survival was not observed in prior series of sinonasal melanomas [7,12]. KIT mutation has been reported to be a marker of better progression-free survival in vulvar melanomas [11].…”

“…In a series of 444 mucosal melanomas from a European population investigated by Sanger sequencing, NRAS, KIT and BRAF mutations were evenly distributed across the different mucosal melanoma subgroups [8]. The prognostic role of these commonly recurrent mutations in mucosal melanomas has only been studied in some series [6,7,11,12]. In a large series of 706 mucosal melanomas, KIT and BRAF mutational status did not correlate with overall survival (OS); however, NRAS was not analyzed in this series [6].…”