This study, covering more than 95% of the uveal melanoma cases in the Swedish population revealed an improvement in relative survival rates for patients with uveal melanoma over time and a significant excess mortality up to 5.5 years after diagnosis.

Purpose: A significant proportion of mucosal melanomas contain alterations in KIT. The aim of this study was to characterize the pattern of KIT, NRAS, and BRAF mutations in mucosal melanomas at specific sites and to assess activation of the KIT downstream RAF/MEK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in mucosal melanoma specimens.Experimental Design: Seventy-one primary mucosal melanomas from various sites were studied. Mutation analysis was done by DNA sequencing. Expression of KIT, phosphorylated (p)-ERK, and p-AKT was evaluated by immunohistochemistry.Results: KIT mutations were detected in 35% (8 of 23) of vulvar, 9% (2 of 22) of anorectal, 7% (1 of 14) of nasal cavity, and 20% (1 of 5) of penile melanomas. No KIT mutations were found in 7 vaginal melanomas. The difference in KIT mutation frequency between vulvar and nonvulvar cases was statistically significant (P ¼ 0.014). The overall frequencies of NRAS and BRAF mutations were 10% and 6%, respectively. Notably, vaginal melanomas showed a NRAS mutation rate of 43%. KIT gene amplification (!4 copies), as assessed by quantitative real-time PCR, was observed in 19% of cases. KIT expression was associated with KIT mutation status (P < 0.001) and was more common in vulvar than nonvulvar tumors (P ¼ 0.016). Expression of p-ERK and p-AKT was observed in 42% and 59% of tumors, respectively, and occurred irrespective of KIT/NRAS/BRAF mutation status. NRAS mutation was associated with worse overall survival in univariate analysis.Conclusions: Results show that KIT mutations are more common in vulvar melanomas than other types of mucosal melanomas and that both the RAF/MEK/ERK and PI3K/AKT pathways are activated in mucosal melanoma specimens.

Background:Mucosal melanomas in the head and neck region are most frequently located in the nasal cavity and paranasal sinuses. Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas. The aim was to determine the KIT, NRAS and BRAF mutation frequencies in a large series of primary SNMMs.Methods:Laser capture microdissection was used to isolate tumour cells from 56 formalin-fixed paraffin-embedded tumours. The tumour cells were screened for KIT, NRAS and BRAF mutations by direct sequencing.Results:Overall, 21% (12 out of 56) of SNMMs harboured KIT, NRAS or BRAF mutations. Mutations in these oncogenes occurred in a mutually exclusive manner. Both KIT and BRAF mutations were identified at a similar frequency of 4% each (2 out of 56), whereas NRAS mutations were detected in 14% (8 out of 56) of the SNMMs. Four of the NRAS mutations were located in exon 1. Mutations in these oncogenes were significantly more common in melanomas located in the paranasal sinuses than in nasal cavity (P=0.045). In a multivariate analysis, patients with melanomas in the nasal cavity had a significantly better overall survival than those with tumours in the paranasal sinuses (P=0.027).Conclusion:Our findings show that KIT and BRAF mutations, which are accessible for present targeted therapies, are only rarely present in SNMMs, whereas NRAS mutations seem to be relatively more frequent. The data show that majority of SNMMs harbour alterations in genes other than KIT, NRAS and BRAF.

Ras mutations, preferentially in codon 61 of the N-ras oncogene, are common in human cutaneous melanomas. In this study, we questioned the association between ras mutations in primary melanomas and sun exposure. DNA was extracted from formalin-fixed primary melanomas: 28 at chronically sun-exposed head and neck areas, 18 at sites subject to intermittent sun exposure, and 28 from unexposed mucosal membranes (vulva/vagina, anus/ rectum, palate). Mutations of both exons of H-, K-, and N-ras genes were examined by polymerase chain reaction/single-strand conformation polymorphism and by direct nucleotide sequencing of the polymerase chain reaction amplified exons. Thirty-two per cent of the head and neck melanomas and 11% of the melanomas from intermittently sun-exposed skin had N-ras codon 61 mutations; comparatively only 7% of the tumors from the unexposed areas had such mutations. One vulvar melanoma had an N-ras codon 12 mutation. No H-ras or K-ras mutations were detected in any sample. The frequency of N-ras exon 2 mutations in melanomas of typically sunbathed skin was compared for the first time with that in melanomas of areas completely protected from sun exposure. The significantly higher frequency (p = 0.04, chi square exact test) of these N-ras mutations on the head and neck demonstrates their UV-light induction in a subset of melanomas explaining one of the molecular effects of UV light in human skin.