<i><scp>NF</scp>1</i>‐mutated melanoma tumors harbor distinct clinical and biological characteristics

Cirenajwis, Helena; Lauss, Martin; Ekedahl, Henrik; Törngren, Therese; Kvist, Anders; Saal, Lao H.; Olsson, Håkan; Staaf, Johan; Carneiro, Ana; Ingvar, Christian; Harbst, Katja; Hayward, Nicholas K.; Jönsson, Göran

doi:10.1002/1878-0261.12050

Cited by 120 publications

(144 citation statements)

References 40 publications

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“…We did not observe any difference between those with one or two truncating NF1 mutations, or with accompany loss of the wild-type allele. Prior literature has suggested an enrichment for co-occurring mutations in Rasopathy genes, particularly PTPN11 and RASA2 (Arafeh et al, 2015; Cirenajwis et al, 2017; Krauthammer et al, 2015) However, we observed co-occurrence of deleterious mutations across numerous genes without specific enrichment, including those that have not been previously implicated as co-mutated with NF1 , although known to be mutated in melanoma, MAP3K5 and MAP3K9 . Functional studies of BRAF wt /RAS wt melanoma cell lines lacking NF1 expression, or expressing NF1 at extremely low levels, have shown that not all have RAS activation and that only some were sensitive to MEKi (Krauthammer et al, 2015).…”

Section: Discussioncontrasting

confidence: 74%

Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines

et al. 2017

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Summary Tumor sequencing studies have revealed the widespread genetic diversity of melanoma. Sequencing of 108 genes previously implicated in melanomagenesis was performed on 462 patient-derived xenografts (PDX), cell lines and tumors to identify mutational and copy number aberrations. Samples came from 371 unique individuals; 263 were naïve to treatment, and 108 were previously treated with targeted therapy (34), immunotherapy (54) or both (20). Models of all previously reported major melanoma subtypes (BRAF, NRAS, NF1, KIT and WT/WT/WT) were identified. Multiple minor melanoma subtypes were also recapitulated, including melanomas with multiple activating mutations in the MAPK signaling pathway and chromatin remodeling gene mutations. These well-characterized melanoma PDX and cell lines can be used not only as reagents for large array of biological studies, but also as pre-clinical models to facilitate drug development.

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Section: Discussioncontrasting

confidence: 74%

Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines

et al. 2017

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“…Mutations in NF1 were mostly mutually exclusive with those in BRAF or NRAS although exact frequencies were not given (Scholz et al, ). These recent findings are also consistent with CM where NF1 mutations occur in 12%–30%, and are generally mutually exclusive from tumors with BRAF and NRAS mutations (Cirenajwis et al, ; Hodis et al, ; Krauthammer et al, ). In line with CM, a 4‐group gene‐specific mutation/triple wild type (wt) classification for CoM was proposed (Cancer Genome Atlas, Network, ; Scholz et al, ).…”

Section: Introductionsupporting

confidence: 75%

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

Kenawy

Kalirai

Sacco

et al. 2019

Pigment Cell Melanoma Res

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Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation‐specific copy number alterations. Deletions on chr 10q11.21‐26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann–Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.

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“…Furthermore, differences between previous studies and the present study may be due to the absence of investigation of LVI and necrosis in many of the above-mentioned studies. However, various molecular alterations accompanying the BRAF V600 mutation may also be features of an ordinary nevus, such as promoter mutations of telomerase reverse transcriptase (TERT) (27,28); mutations in NRAS, PTEN, CDK2NA, STK19, KIT, GNAQ, GNA11 and NF 1 genes (29)(30)(31) or undetected interactions between the BRAF V600 mutation and other signaling pathways (26). Further studies on genotypic and phenotypic alterations in specimens of primary tumours obtained from both metastatic and nonmetastatic patients may provide more information about the impact of the BRAF mutation on prognostic features of melanoma.…”

Section: Discussionmentioning

confidence: 99%

Braf v600 mutation profile of metastatic melanoma in the thrace region of turkey

Can¹,

Taştekin²,

Yalta³

et al. 2018

TJPATH

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Objective: BRAF is the most common mutation in melanoma. The most common subtype is BRAF V600E, followed by V600K. Initially, the authors aimed to investigate whether clinicopathological features of melanoma are associated with BRAF mutations. We then aimed to present the relationships between the clinicopathological features and the mutated subtype (V600E vs V600K). Material and Method:61 patients with metastatic malignant melanoma (affecting the lymph node or other distant sites) were selected. Patient data regarding age at the time of diagnosis, sex, metastatic site (lymph node, distant metastasis or both) and primary tumour site were obtained from the hospital's database. Tissue samples containing at least 30% tumour cells were isolated from the specimens of 61 patients (24 samples from primary tumours and 37 from metastatic foci) for BRAF analysis. Comparisons between the BRAF V600 mutation and clinicopathological and histopathological features were performed.Results: BRAF V600 mutation was detected in 34 (55.7%) patients. The subtype was BRAF V600E in 22 (64.7%) patients, BRAF V600K in 11(32.4%) patients and BRAF V600R in 1(2.9%) patient. The crucial results of the present study may be summarized as follows: i) BRAF V600 mutation was more common in older patients and tumors with BRAF V600 mutation revealed necrosis and LVI more commonly than wild-type tumors, ii) BRAF V600K mutation was more common in older patients and BRAF V600K mutated tumors exhibited ulceration more commonly than tumors with BRAF V600E mutation (close to significant). Conclusion:The BRAF V600 mutation may have interactions with prognostic clinicoptahological features of melanoma including necrosis and lymphovascular invasion. V600K mutation may be more common than expected and may have different associations with properties of the tumor such as tumor ulceration and patient age. Investigation of the mutated subtype of the BRAF gene may therefore reveal more detailed data about the management of melanoma and may also prevent missing of candidates for BRAF inhibitor therapies.

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NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

Cited by 120 publications

References 40 publications

Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines

Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

Braf v600 mutation profile of metastatic melanoma in the thrace region of turkey

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