Clinical and therapeutic implications of <i><scp>BRAF</scp></i> mutation heterogeneity in metastatic melanoma

Ardakani, Nima Mesbah; Leslie, Connull; Grieu-Iacopetta, Fabienne; Lam, Wei-Sen; Budgeon, Charley; Millward, Michael; Amanuel, Benhur

doi:10.1111/pcmr.12569

Cited by 18 publications

(12 citation statements)

References 31 publications

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“…Taken together, such differential results may reflect the high degree of intra-tumoral heterogeneity often observed with BRAF V600E mutations. This aspect has been noted in previous studies [31][32][33].…”

Section: Discussionsupporting

confidence: 85%

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes

Betancourt¹,

Szász²,

Kuras³

et al. 2019

Preprint

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In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas do clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression for the mutated protein is associated with a more aggressive tumor progression. Our study design that is comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis may enable the eventual delineation of patient responders/non-responders and the subsequent therapy of malignant melanoma.

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Section: Discussionsupporting

confidence: 85%

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes

Betancourt¹,

Szász²,

Kuras³

et al. 2019

Preprint

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“… Samples Methods Number (%) of Heterogeneous Tumors Overall Among BRAF Mutated Tumors [76] 5 PT scPCR, Sanger seq 4/5 (80%) 4/4 (100%) [85] 49 PT IHC 29/49 (59%) 29/31 (94%) [86] 50 PT 139 MT HRM, qPCR, IHC 25/189 (13%) 25/88 (28%) [87] 20 PT IHC 2/20 (10%) 2/7 (29%) [88] 100 PT PNA qPCR, IHC, NGS, Cap seq 7/100 (7%) 7/59 (12%) [89] 124 PT 76 MT IHC 10/200 (5%) 10/94 (11%) [90] 22 MI1S 56 PT 93 MT Pyro, IHC 2/171 (1%) 2/75 (3%) [91] 140 PT 171 MT IHC 0/239 (0%) 0/137 (0%) Overall 79/973 (8.1%) 79/495 (16.0%) [63] 104 NT from TCGA NGS BRAF-M% ranged from 8% to 97% [92] 75 PT 88 MT NGS BRAF-M% ranged from 0% to 92% (median for PT: 28% and for MT: 26%) [63] 475 NT Pyro, qPCR, dPCR BRAF-M% ranged from 10% to 90%. [93] 9 PT LCM, Direct seq, SNaPshot assay BRAF-M% ranged from 0% to 81% [94] 52 MT ...…”

Section: Intratumor Heterogeneity In Melanomamentioning

confidence: 99%

“…Therefore, it is necessary to perform an analysis of multiple biopsies within all tumors with very high accuracy to detect rare mutations present commonly in small subclones. Due to intratumor heterogeneity, a single biopsy may be insufficient for the evaluation of the alterations landscape of the whole tumor [15] , [33] , [67] , [94] , [103] , [108] , [205] . For instance, Lake et al [113] established that biopsies of an extraocular, thereby more accessible, part of UM may not represent a whole tumor spectrum of mutations.…”

Section: Implications For Diagnosis and Treatmentmentioning

confidence: 99%

Intratumor and Intertumor Heterogeneity in Melanoma

Grzywa

Paskal

Włodarski

2017

Translational Oncology

244

216

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Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. The incidence rate escalates. A high number of clones harboring various mutations contribute to an exceptional level of intratumor heterogeneity of melanoma. It also refers to metastases which may originate from different subclones of primary lesion. Such component of the neoplasm biology is termed intertumor and intratumor heterogeneity. These levels of tumor heterogeneity hinder accurate diagnosis and effective treatment. The increasing number of research on the topic reflects the need for understanding limitation or failure of contemporary therapies. Majority of analyses concentrate on mutations in cancer-related genes. Novel high-throughput techniques reveal even higher degree of variations within a lesion. Consolidation of theories and researches indicates new routes for treatment options such as targets for immunotherapy. The demand for personalized approach in melanoma treatment requires extensive knowledge on intratumor and intertumor heterogeneity on the level of genome, transcriptome/proteome, and epigenome. Thus, achievements in exploration of melanoma variety are described in details. Particularly, the issue of tumor heterogeneity or homogeneity given BRAF mutations is discussed.

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“…For these individuals, the addition of BRAF targeted therapy to the radiation treatment was shown to have significant benefit, thus making the potential establishment of a noninvasive diagnostic method even more valuable 37 . In addition, recent evidence has demonstrated a discrepancy between the genetics of the primary tumor and its CNS metastasis in 13.4% of cases and in 7% of lesions in patients with polymetastatic disease 38,39 . Thus, the need for the development of a noninvasive tool that allows sequential evaluation of the genetic status of multiple metastases is clear.…”

Section: Discussionmentioning

confidence: 99%

Virtual biopsy using MRI radiomics for prediction of BRAF status in melanoma brain metastasis

Shofty

Artzi

Shtrozberg

et al. 2020

Sci Rep

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Brain metastases are common in patients with advanced melanoma and constitute a major cause of morbidity and mortality. Between 40% and 60% of melanomas harbor BRAF mutations. Selective BRAf inhibitor therapy has yielded improvement in clinical outcome; however, genetic discordance between the primary lesion and the metastatic tumor has been shown to occur. currently, the only way to characterize the genetic landscape of a brain metastasis is by tissue sampling, which carries risks and potential complications. the aim of this study was to investigate the use of radiomics analysis for non-invasive identification of BRAF mutation in patients with melanoma brain metastases, based on conventional magnetic resonance imaging (MRi) data. We applied a machine-learning method, based on MRi radiomics features for noninvasive characterization of the BRAf status of brain metastases from melanoma (BMM) and applied it to BMM patients from two tertiary neuro-oncological centers. All patients underwent surgical resection for BMM, and their BRAf mutation status was determined as part of their oncological work-up. their routine preoperative MRi study was used for radiomicsbased analysis in which 195 features were extracted and classified according to their BRAF status via a support vector machine. The BRAF status of 53 study patients, with 54 brain metastases (25 positive, 29 negative for BRAF mutation) was predicted with mean accuracy = 0.79 ± 0.13, mean precision = 0.77 ± 0.14, mean sensitivity = 0.72 ± 0.20, mean specificity = 0.83 ± 0.11 and with a 0.78 area under the receiver operating characteristic curve for positive BRAf mutation prediction. Radiomics-based noninvasive genetic characterization is feasible and should be further verified using large prospective cohorts. Melanoma is the third most common cutaneous tumor after basal cell carcinoma and squamous cell carcinoma. Melanomas account for up to 1.6% of newly diagnosed malignancies in the developed world 1. The worldwide incidence of malignant melanoma is rising, with approximately 290,000 new cases diagnosed per year, resulting in up to 60,000 mortalities 2. Systemic melanoma carries a high risk of central nervous system (CNS) spread 3. Up to 75% of stage IV patients with systemic melanoma eventually develop CNS metastases, which account for up to 50% of melanoma-related mortalities 4,5. The risk of brain metastases from melanoma (BMM) rises with disease duration. While 20-30% of patients will develop BMM in one year, 30-40% will develop BMM in 3 years 6. Identification of BRAF activating mutation as a key oncogene in approximately half of all melanomas has dramatically changed the current treatment strategy for metastatic melanoma 7-10. BRAF mutation has been assumed to be an early evolutionary event in tumor maturation, and play a central role in melanoma pathogenesis 11. At the cellular level, BRAF mutations drive oncogenic behavior of melanoma cells, leading to unrestricted cell growth, increased cell survival, and local invasion through activation of the mitogen-...

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Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma

Cited by 18 publications

References 31 publications

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes

Intratumor and Intertumor Heterogeneity in Melanoma

Virtual biopsy using MRI radiomics for prediction of BRAF status in melanoma brain metastasis

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Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma

Cited by 18 publications

References 31 publications

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma &ndash; Association with Clinical Outcome and Tumor Phenotypes

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma &ndash; Association with Clinical Outcome and Tumor Phenotypes

Intratumor and Intertumor Heterogeneity in Melanoma

Virtual biopsy using MRI radiomics for prediction of BRAF status in melanoma brain metastasis

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Product

Resources

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The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes