The role of<i>BRAF</i>mutations in primary melanoma growth rate and survival

Mar, Victoria; Liu, Wenyuan; Devitt, Bianca; Wong, Stephen Q.; Dobrovic, Alexander; McArthur, Grant A.; Wolfe, Rory; Kelly, John W.

doi:10.1111/bjd.13756

Cited by 37 publications

(32 citation statements)

References 35 publications

(62 reference statements)

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“…Nonetheless, this tendency to shorter survival in V600K subjects is consistent with literature findings that V600K tumors tend to have less favorable outcomes than V600E tumors [4, 8–11, 13]. …”

Section: Resultssupporting

confidence: 91%

“…Patients with V600K tumors appear to be older (over 50) males, and the tumors often occur in the head and neck area (prone to sun damage) [4, 7–13]. Pathologically, V600K tumors appear to be thicker and are more mitotically active than V600E tumors [8]. Clinically, patients with V600K tumors have an increased risk for brain and lung metastases and are at a siginficantly increased risk of relapse and have a shorter time from diagnosis to metastasis than those with V600E tumors [4, 8–11, 13].…”

Section: Introductionmentioning

confidence: 99%

“…Pathologically, V600K tumors appear to be thicker and are more mitotically active than V600E tumors [8]. Clinically, patients with V600K tumors have an increased risk for brain and lung metastases and are at a siginficantly increased risk of relapse and have a shorter time from diagnosis to metastasis than those with V600E tumors [4, 8–11, 13]. Despite those differences, a large clinical trial showed that V600K tumors were sensitive to vemurafenib, a BRAF inhibitor, and that patients with V600K or V600E tumors, when treated with vemurafenib, had similar overall survival and progression-free survival outcomes [10].…”

Section: Introductionmentioning

confidence: 99%

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Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma

Umbach²,

Li³

2017

Melanoma Research

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Approximately, 50% of all cutaneous melanomas harbor activating BRAF V600 mutations, among these 10–30% carry the V600K mutation. Clinically, patients with V600K tumors experience distant metastases sooner and have an increased risk of relapse and shorter survival than patients with V600E tumors. Despite clinical and other histopathological differences between these BRAF tumor subtypes, little is known about them at the genomic level. Herein, we systematically compared BRAF V600E and V600K skin cutaneous melanoma (SKCM) samples from the Cancer Genome Atlas (TCGA) for differential protein, gene, and microRNA expression genome-wide using the Mann-Whitney U-test. Our analyses showed that elements of energy-metabolism and protein-translation pathways were up-regulated and that pro-apoptotic pathways were down-regulated in V600K tumors compared to V600E tumors. We found that c-Kit protein and KIT gene expressions were significantly higher in V600K tumors than in V600E tumors, concurrent with significant down-regulation of several KIT-targeting microRNAs (mir) including mir-222 in V600K tumors, suggesting KIT and mir-222 might key genomic contributors to observed clinical differences. The relationship that we uncovered among KIT/c-Kit expression, mir-222 expression, and growth and pro-survival signals in V600 tumors is intriguing. We believe that the observed clinical aggressiveness of V600K tumors compared to V600E tumors may be attributable to the increased energy-metabolism, protein-translation and pro-survival signals compared to V600E tumors. If confirmed using larger numbers of V600K tumors, our results may prove useful for designing clinical management and targeted chemotherapeutical interventions for BRAF V600K positive melanomas. Lastly, small sample size in V600K tumors is a major limitation of our study.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma

Umbach²,

Li³

2017

Melanoma Research

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“…The BRAF V600E mutation has been identified in 40% to 45% of metastatic melanomas in prospective studies with comprehensive interrogation (23,24). This mutation is considered an oncogenic driver, and melanomas bearing these BRAF V600E alterations have excellent responses to BRAF inhibitors such as vemurafenib or dabrafenib (26,27); these responses are entirely comparable with the most effective single-agent, oncogene-targeted therapies in non–small lung cancer (EGFR and ALK inhibitors in patients with corresponding actionable alterations) (33–36).…”

Section: Brafmentioning

confidence: 99%

The Conundrum of Genetic “Drivers” in Benign Conditions

Kato

Lippman

Flaherty

et al. 2016

JNCI J Natl Cancer Inst

125

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Advances in deep genomic sequencing have identified a spectrum of cancer-specific passenger and driver aberrations. Clones with driver anomalies are believed to be positively selected during carcinogenesis. Accumulating evidence, however, shows that genomic alterations, such as those in BRAF, RAS, EGFR, HER2, FGFR3, PIK3CA, TP53, CDKN2A, and NF1/2, all of which are considered hallmark drivers of specific cancers, can also be identified in benign and premalignant conditions, occasionally at frequencies higher than in their malignant counterparts. Targeting these genomic drivers can produce dramatic responses in advanced cancer, but the effects on their benign counterparts are less clear. This benign-malignant phenomenon is well illustrated in studies of BRAF V600E mutations, which are paradoxically more frequent in benign nevi (∼80%) than in dysplastic nevi (∼60%) or melanoma (∼40%-45%). Similarly, human epidermal growth factor receptor 2 is more commonly overexpressed in ductal carcinoma in situ (∼27%-56%) when compared with invasive breast cancer (∼11%-20%). FGFR3 mutations in bladder cancer also decrease with tumor grade (low-grade tumors, ∼61%; high-grade, ∼11%). “Driver” mutations also occur in nonmalignant settings: TP53 mutations in synovial tissue from rheumatoid arthritis and FGFR3 mutations in seborrheic keratosis. The latter observations suggest that the oncogenicity of these alterations may be tissue context–dependent. The conversion of benign conditions to premalignant disease may involve other genetic events and/or epigenetic reprogramming. Putative driver mutations can also be germline and associated with increased cancer risk (eg, germline RAS or TP53 alterations), but germline FGFR3 or NF2 abnormalities do not predispose to malignancy. We discuss the enigma of genetic “drivers” in benign and premalignant conditions and the implications for prevention strategies and theories of tumorigenesis.

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“…[11,12] These oncogenic drivers in the NRAS Q61K promote invasiveness of the malignant cells and have larger nodal involvement when compared to the BRAF mutations. [13] RXRα plays a major role in gene expression and signal transduction and in human melanomas the expression of RXRα is lost as the disease progresses. [14] Animal studies have indicated that the loss of RXRα in skin keratinocytes can lead to the increased melanocyte proliferation and the formation of malignant melanomas.…”

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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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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The role ofBRAFmutations in primary melanoma growth rate and survival

Abstract: The presence of a BRAF mutation does not necessarily 'drive' more rapid tumour growth but is associated with poorer MSS in patients with early-stage disease.

Cited by 37 publications

References 35 publications

Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma

Putative genomic characteristics of BRAF V600K versus V600E cutaneous melanoma

The Conundrum of Genetic “Drivers” in Benign Conditions

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

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