The hidden story of heterogeneous B-raf V600E mutation quantitative protein expression in metastatic melanoma—association with clinical outcome and tumor phenotypes

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Bibtex

@article{7ac9c379b1384d81b0912904ee862047,
title = "The hidden story of heterogeneous B-raf V600E mutation quantitative protein expression in metastatic melanoma—association with clinical outcome and tumor phenotypes",
abstract = "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 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 in the mutated protein is associated with a more aggressive tumor progression. Our study design, comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis, may enable the eventual delineation of patient responders/non-responders and subsequent therapy for malignant melanoma.",
keywords = "BRAF V600E mutation, Heterogeneity, Malignant melanoma, Mass spectrometry genetics, Prognosis, Proteomics",
author = "Betancourt, {Lazaro Hiram} and Szasz, {A. Marcell} and Magdalena Kuras and Murillo, {Jimmy Rodriguez} and Yutaka Sugihara and Indira Pla and Zsolt Horvath and Krzysztof Paw{\l}owski and Melinda Rezeli and Kenichi Miharada and Jeovanis Gil and Jonatan Eriksson and Roger Appelqvist and Tasso Miliotis and Bo Baldetorp and Christian Ingvar and H{\aa}kan Olsson and Lotta Lundgren and Peter Horvatovich and Charlotte Welinder and Elisabet Wieslander and Kwon, {Ho Jeong} and Johan Malm and Nemeth, {Istvan Balazs} and G{\"o}ran J{\"o}nsson and David Feny{\"o} and Aniel Sanchez and Gy{\"o}rgy Marko-Varga",
year = "2019",
doi = "10.3390/cancers11121981",
language = "English",
volume = "11",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "12",

}