Intra-patient heterogeneity of BRAF mutation status: fact or fiction?

Menzies, Alexander M.; Wilmott, James S.; Long, Georgina V.; Scolyer, Richard A.

doi:10.1038/bjc.2013.796

Cited by 8 publications

(10 citation statements)

References 11 publications

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“…Intra‐patient heterogeneity or homogeneity of the BRAF mutational status in melanoma is still a controversial issue and has led to opposing conclusions in different studies . Interestingly, we founded in 2 MMP discordant results for the BRAFV600E status (both by molecular biology and IHC) between the primary and the metastatic tumour sites.…”

Section: Discussionmentioning

confidence: 75%

“…Intra-patient heterogeneity or homogeneity of the BRAF mutational status in melanoma is still a controversial issue and has led to opposing conclusions in different studies. 4,[16][17][18][19][20] Interestingly, we founded in 2 MMP discordant results for the BRAFV600E status (both by molecular biology and IHC) between the primary and the metastatic tumour sites. Although this event was very rare, it supports the possibility of heterogeneity of BRAFV600E mutations in different tumour samples taken from a MMP.…”

Section: Discussionmentioning

confidence: 75%

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Why and how immunohistochemistry should now be used to screen for the BRAFV600E status in metastatic melanoma? The experience of a single institution (LCEP, Nice, France)

Long

Ilié

Lassalle

et al. 2015

Acad Dermatol Venereol

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This study showed that VE1 IHC should be a substitute for molecular biology in the initial assessment of the BRAFV600E status in MPP. This methodology needs to be set up in pathology laboratories in accordance with quality control/quality assurance accreditation procedures. Under these strict conditions the question is to know if BRAFV600E-IHC can serve not only as a prescreening tool, but also as a stand-alone test (at least in cases displaying an unequivocally staining pattern) as well as an alternative predictive test for samples for which the molecular biology failed.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 75%

Why and how immunohistochemistry should now be used to screen for the BRAFV600E status in metastatic melanoma? The experience of a single institution (LCEP, Nice, France)

Long

Ilié

Lassalle

et al. 2015

Acad Dermatol Venereol

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“…In contrast, studies using immunohistochemical (IHC) detection of BRAF mutant protein ( BRAF VE1 antibody) suggest intratumoral as well as intertumoral BRAF homogeneity in patients with multiple metastatic deposits based on direct visualization of melanoma cells in the tissue sections (Menzies et al., ; Riveiro‐Falkenbach et al., ). Despite this reported homogeneity, the IHC‐based studies have affirmed that there is some degree of heterogeneity in staining intensity (Eriksson et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…BRAF mutation has been assumed to be an early event in tumour progression in a subset of melanomas. Studies based on immunohistochemical analysis of melanoma tumour samples utilizing the VE1 antibody have often shown a relatively homogenous expression pattern (Menzies et al., ; Riveiro‐Falkenbach et al., ) across different tumour samples. However, molecular‐based studies have demonstrated intratumoral and intertumoral heterogeneity (Heinzerling et al., ; Lin et al., ) in mutation status and type.…”

Section: Introductionmentioning

confidence: 99%

Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma

Ardakani

Leslie

Grieu-Iacopetta

et al. 2017

Pigment Cell Melanoma Res

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Heterogeneity of BRAF mutation in melanoma has been a controversial subject. Quantitative data on BRAF allele frequency (AF) are sparse, and the potential relationship with response to BRAF inhibitors (BRAFi) in patients with metastatic melanoma is unknown. We quantitatively measured BRAF AF in a cohort of treatment naïve metastatic melanoma samples by pyrosequencing and correlated with survival data in patients treated with BRAFi as part of their clinical care. Fifty-two samples from 50 patients were analysed. BRAF V600E mutations were detected in 71.1% of samples followed by V600K (25%) and V600R (3.9%). There was a wide range of AF from 3.9% to 80.3% (median 41.3%). In 33 patients treated with BRAFi, there was no difference in overall or progression-free survival when the patients were categorized into high or low AF groups. There was no correlation between AF and degree of response, and no difference in survival based on genotype.

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“…The intrapatient tumor heterogeneity in melanomas was recently questioned; however, it seems that this question is inherent to the method sensitivity. 21,22 Until now, only qualitative methods were used to evaluate BRAF mutation status in clinical trials. However, it could be interesting to quantify also the mutation load.…”

Section: Discussionmentioning

confidence: 99%

Next-Generation Genotyping by Digital PCR to Detect and Quantify the BRAF V600E Mutation in Melanoma Biopsies

Lamy

Castan

Lozano

et al. 2015

The Journal of Molecular Diagnostics

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The detection of the BRAF V600E mutation in melanoma samples is used to select patients who should respond to BRAF inhibitors. Different techniques are routinely used to determine BRAF status in clinical samples. However, low tumor cellularity and tumor heterogeneity can affect the sensitivity of somatic mutation detection. Digital PCR (dPCR) is a next-generation genotyping method that clonally amplifies nucleic acids and allows the detection and quantification of rare mutations. Our aim was to evaluate the clinical routine performance of a new dPCR-based test to detect and quantify BRAF mutation load in 47 paraffin-embedded cutaneous melanoma biopsies. We compared the results obtained by dPCR with highresolution melting curve analysis and pyrosequencing or with one of the allele-specific PCR methods available on the market. dPCR showed the lowest limit of detection. dPCR and allele-specific amplification detected the highest number of mutated samples. For the BRAF mutation load quantification both dPCR and pyrosequencing gave similar results with strong disparities in allele frequencies in the 47 tumor samples under study (from 0.7% to 79% of BRAF V600E mutations/sample). In conclusion, the four methods showed a high degree of concordance. dPCR was the more-sensitive method to reliably and easily detect mutations. Both pyrosequencing and dPCR could quantify the mutation load in heterogeneous tumor samples. (J Mol Diagn 2015, 17: 366e373; http://dx.Mutations and chromosomal translocations underlie key molecular mechanisms that can drive cancer development/ progression. Therefore, treatment strategies that target specific molecules related to gene mutations or chromosome rearrangements were developed. For instance, the BRAF gene encodes the BRAF protein, a cytoplasmic serine/threonine protein kinase that is involved in regulating signaling pathway. BRAF gene mutations are detected in several malignancies, including colorectal, lung, and thyroid cancer and in nearly all cases of classic hairy-cell leukemia. 1e3 BRAF somatic missense mutations are also present in most malignant melanomas. Specifically, approximately 75% of melanoma samples harbor the BRAF V600E-activating mutation. 4 Importantly, treatment with the BRAF inhibitor vemurafenib shows an 80% response rate in patients with BRAF V600E-positive metastatic melanoma. 5 The identification of diagnostic somatic chromosomal/genetic abnormalities, such as the BRAF V600E-activating mutation, is thus becoming of crucial importance in the field of personalized cancer treatments, because it can guide the therapeutic decisions and can predict therapeutic responses.Many techniques can be used to detect somatic mutations. The gold standard for mutation detection is the Sanger technique that is performed on automated DNA sequencing instruments. However, the low sensitivity of somatic mutation

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Intra-patient heterogeneity of BRAF mutation status: fact or fiction?

Cited by 8 publications

References 11 publications

Why and how immunohistochemistry should now be used to screen for the BRAFV600E status in metastatic melanoma? The experience of a single institution (LCEP, Nice, France)

Why and how immunohistochemistry should now be used to screen for the BRAFV600E status in metastatic melanoma? The experience of a single institution (LCEP, Nice, France)

Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma

Next-Generation Genotyping by Digital PCR to Detect and Quantify the BRAF V600E Mutation in Melanoma Biopsies

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