Dataset Information

KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases.

ABSTRACT:

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.

SUBMITTER: Zebary A

PROVIDER: S-EPMC3738146 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Publications

KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases.

Zebary A A Jangard M M Omholt K K Ragnarsson-Olding B B Hansson J J

British journal of cancer 20130716 3

<h4>Background</h4>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.<h4>Methods</h4>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 b ...[more]

PMID: 23860532

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Project description:BackgroundMelanoma frequently harbors BRAF, NRAS, or KIT mutations which influence both tumor development and treatment strategies. For example, it is still controversial whether adjuvant anti-PD-1 monotherapy or BRAF/MEK inhibitors may better improve the survival for resected BRAF-mutant melanoma. Furthermore, outcomes for melanoma with NRAS and KIT mutation receiving adjuvant immunotherapy remain unclear.MethodsOne hundred seventy-four stage III melanoma patients who underwent radical surgery in Fudan University Shanghai Cancer Center (FUSCC) during January 2017 to December 2021 were included in this real-world study. Patients were followed up until death or May 30th, 2022. Pearson's chi-squared test or Fisher's exact test was performed for univariable analysis of the different category groups. Log-rank analysis was used to identify the prognostic factors for disease-free survival (DFS).ResultsThere were 41 (23.6%) patients with BRAF mutation, 31 (17.8%) with NRAS mutation, 17 (9.8%) with KIT mutation, and 85 (48.9%) wild-type patients without either genomic alteration of those three genes. Most ( n = 118, 67.8%) of them were acral melanoma, while 45 (25.9%) were cutaneous subtype, and 11 were (6.3%) primary unknown. Among them, 115 (66.1%) patients received pembrolizumab or toripalimab monotherapy as adjuvant therapy; 22 (12.6%) patients received high-dose interferon (IFN), and 37 (21.3%) patients were just for observation. There was no statistical difference in clinicopathologic factors between anti-PD-1 group and IFN/OBS group. Of all the enrolled patients, anti-PD-1 group had a better DFS than IFN/OBS group ( p = 0.039). In anti-PD-1 group, patients with BRAF or NRAS mutations had poorer DFS than wild-type group. No survival difference was found among patients harboring different gene mutations in IFN/OBS group. In wild-type patients, anti-PD-1 group had a better DFS than IFN/OBS group ( p = 0.003), while no survival benefits were found for patients with BRAF, NRAS, or KIT mutations.ConclusionAlthough anti-PD-1 adjuvant therapy provides a better DFS in the general population and in wild-type patients, patients with BRAF, KIT or, especially, NRAS mutation may not benefit further from immunotherapy than conventional IFN treatment or observation.

Project description:BackgroundHotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear.MethodsThe mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing. The genotypes were correlated with clinical outcomes and pathologic features of the primary tumors. Time to disease progression was calculated with the cumulative incidence function. Survival analyses were performed with Kaplan-Meier estimates and Cox proportional hazards regression analysis. Relative survival was calculated with the Ederer-II method. Treatment with BRAF and MEK inhibitors and immune checkpoint blockade (ICB) was allowed.ResultsMutations in BRAF and NRAS were identified in 40.1 and 24.4% of cases, respectively. Concurrent mutations in both genes were detected in further 2.3%. The remaining 33.2% were wild type for the investigated exons (WT). BRAF mutations were significantly associated with younger age at first diagnosis (p?<?0.001) and truncal localization of the culprit primary (p?=?0.002). The nodular subtype was most common in the NRAS cohort. In addition, NRAS-mutant melanoma patients showed a higher frequency of nodal relapse (p?=?0.013) and development of metastatic disease (p?=?0.021). The time to loco-regional nodal relapse was shortest in NRAS-mutant melanoma (p?=?0.002). Presence of NRAS mutation was an independent risk factor for disease progression in multivariate analysis (HR 2.01; 95% CI 1.02?-?3.98). BRAF-mutant melanoma patients showed a tendency for better overall and relative survival. Genotype was not a consistent risk factor in multivariate analysis. Instead, positive sentinel lymph node status (HR 2.65; 95% CI 1.15?-?6.10) and treatment with ICB in stage IV disease (HR 0.17; 95% CI 0.06-0.48) were significant multivariate risk factors.ConclusionsNRAS-mutant tumors tended to behave more aggressively particularly in early stages of the disease in this high-risk melanoma population. Treatment with immune checkpoint blockade improved survival in stage IV disease in a real-world setting.

Dataset Information

KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases.

Background

Methods

Results

Conclusion

Publications

KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases.

Similar Datasets

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