Prognostic and predictive values of oncogenic <i>BRAF, NRAS, c‐KIT</i> and <i>MITF</i> in cutaneous and mucous melanoma

Pracht, Marc; Mogha, Ariane; Lespagnol, Alexandra; Fautrel, Alain; Mouchet, Nicolas; Gall, Florence Le; Paumier, Veronique; Lefeuvre-Plesse, Claudia; Rioux-Leclerc, Nathalie; Mosser, Jean; Oger, Emmanuel; Adamski, H.; Galibert, M.D.; Lesimple, Thierry

doi:10.1111/jdv.12910

Cited by 41 publications

(34 citation statements)

References 45 publications

(79 reference statements)

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“…[4][5][6][7][8]11 with the activating NRAS mutation in the melanocytes, represent a metastatic melanoma model…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…The majority studied mutations occur primarily in the BRAF (a serine/threonine protein kinase) genes and have approved targeted therapies for patients in stage IV or unresectable melanoma. [4,5] However, newer emerging genetic targets include Neuroblastoma -Rat Sarcoma (NRAS) [4][5][6] and nuclear receptors like Retinoid X Receptor-α (RXRα) genes. [7,8] In pathological conditions, point mutations at the codon 61 of NRAS (NRASQ 61K ) gene locks the activated form of NRAS-GTP thereby promoting continuous up regulation of downstream effector proteins and signaling pathways in the malignant melanoma phenotype.…”

Section: Introductionmentioning

confidence: 99%

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A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Doddapaneni

Kyryachenko

Chagani

et al. 2015

Journal of Controlled Release

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Metastatic Melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NP) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NP are similarly sized (~ 48nm), with neutral, partially charged, or fully charged surface. The NP are able to load ~ 2mg/mL of each drug and are stable for 24 h. The NP are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NP were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NP are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NP are efficacious at the proximal LN, while the fully charged NP have no effect on either LN. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NP have the highest potential in treating metastatic melanoma. GRAPHICAL ABSTRACT

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“…[4][5][6][7][8]11 with the activating NRAS mutation in the melanocytes, represent a metastatic melanoma model…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Doddapaneni

Kyryachenko

Chagani

et al. 2015

Journal of Controlled Release

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“…BRAF mutations have been extensively reported in melanomas and, interestingly, these mutations are more frequently reported in melanomas arising in non-chronic sun-damaged skin [39,40]. In a recent series of 66 intraoral squamous cell carcinoma of the tongue, only 1 sample showed BRAF mutation [41], and in other intraoral squamous cells carcinoma series, BRAF mutation was not detected in any sample [42].…”

Section: Discussionmentioning

confidence: 97%

Lip cancer and pre-cancerous lesions harbor TP53 mutations, exhibit allelic loss at 9p, 9q, and 17p, but no BRAFV600E mutations

et al. 2015

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Molecular mechanisms of lip squamous cell carcinoma (LSCC) and actinic cheilitis (AC) are unclear. We aimed at assessing loss of heterozygosity (LOH) and TP53 and BRAF V600E mutations in these lesions. Formalin-fixed paraffin-embedded (FFPE) samples of 17 LSCC and 16 AC were included, with additional 5 fresh LSCC genotyped for TP53 mutations. LOH was assessed by six polymorphic markers located at 9p22, 9q22, and 17p13 and correlated with cell proliferation (Ki-67) and P53 immunostaining. Direct sequencing of TP53 exons 2-11 (fresh samples), and exons 5-9 (FFPE samples) was carried out. BRAF V600E mutation was genotyped in eight LSCC. LOH occurred in at least one marker in 15/17 LSCC and in 9/16 AC. The marker exhibiting the highest frequency of allelic loss (FAL) in LSCC was D9S157 (8/12 informative cases) and D9S287 in AC (4/11 informative cases). Cell proliferation was not correlated with LOH or with the FAL and no correlation between P53 IHC and 17p LOH was observed. We found TP53 missense mutations in both lesions and nonsense in LSCC, including CC>TT transition, which is a marker of UV damage. BRAF V600E mutation was not detected. LOH and TP53 mutations detected in LSCC and AC may be associated with tumorigenesis, whereas BRAF V600E mutation does not seem to significantly contribute to LSCC pathogenesis.

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“…Previous studies on the associations between BRAF and NRAS mutations and survival of melanoma patients have been inconsistent. (11,23,(28)(29)(30)(31)(32)(33). In our study, all data items were available for the classification describing the state of the primary tumor in the AJCC TNM (tumor, regional nodes, distant metastasis) clinical melanoma staging system (34).…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological characteristics and mutation profile of BRAF and NRAS mutation in cutaneous melanomas in the Western Turkish population

Evrenos¹,

Temız²,

Çam³

et al. 2018

Turk J Med Sci

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Materials and Methods 2.1. Tumor Samples Formalin-fixed paraffin-embedded (FFPE) blocks of patients diagnosed as MM between 2006 and 2013 were Background/aim: Malignant melanoma is the most common cause of death due to skin cancers. The most common mutations in RAF-RAS pathway from tumor oncogenes are BRAF and NRAS. In this study, we analyzed the frequency of BRAF and NRAS gene mutations and investigated their association with clinicopathological features of melanomas in the Turkish population. Materials and methods: 65 primary cutaneous melanoma were included in the study. The mutations were evaluated with real-time PCRbased PCR-array through allele-specific amplification, and the results were correlated with various clinicopathological characteristics. Results: 52.3% of the patients were female and 47.7% were male. The mean age of the patients with a mutation was lower than those without mutation. 16 patients had BRAF mutation. 12 patients had NRAS mutation. NRAS mutation was statistically more common in men (P = 0.036). The number of mitoses increased with the increase of the tumor thickness (P = 0.003). There was more mitosis in the presence of ulceration (P = 0.05). A total of 41.7% of NRAS mutations had adjuvant chemotherapy. Conclusion: We found lower mutation rate when compared to regional studies. NRAS mutation was common in men. This is the first study from our region evaluating the prognostic value of clinical stage and necessity of adjuvant treatment with the presence of BRAF and NRAS mutations.

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Prognostic and predictive values of oncogenic BRAF, NRAS, c‐KIT and MITF in cutaneous and mucous melanoma

Cited by 41 publications

References 45 publications

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Lip cancer and pre-cancerous lesions harbor TP53 mutations, exhibit allelic loss at 9p, 9q, and 17p, but no BRAFV600E mutations

Clinicopathological characteristics and mutation profile of BRAF and NRAS mutation in cutaneous melanomas in the Western Turkish population

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