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

Betancourt, Lazaro Hiram LU ; Szasz, A. Marcell LU ; Kuras, Magdalena LU ; Murillo, Jimmy Rodriguez ; Sugihara, Yutaka LU ; Pla, Indira LU ; Horvath, Zsolt LU ; Pawłowski, Krzysztof LU ; Rezeli, Melinda LU and Miharada, Kenichi LU , et al. (2019) In Cancers 11(12).
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... (More)

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.

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keywords
BRAF V600E mutation, Heterogeneity, Malignant melanoma, Mass spectrometry genetics, Prognosis, Proteomics
in
Cancers
volume
11
issue
12
article number
1981
publisher
Multidisciplinary Digital Publishing Institute (MDPI)
external identifiers
  • pmid:31835364
  • scopus:85076532893
ISSN
2072-6694
DOI
10.3390/cancers11121981
language
English
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yes
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7ac9c379-b138-4d81-b091-2904ee862047
date added to LUP
2020-01-07 13:18:36
date last changed
2020-01-08 14:42:22
@article{7ac9c379-b138-4d81-b091-2904ee862047,
  abstract     = {<p>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.</p>},
  author       = {Betancourt, Lazaro Hiram and Szasz, A. Marcell and Kuras, Magdalena and Murillo, Jimmy Rodriguez and Sugihara, Yutaka and Pla, Indira and Horvath, Zsolt and Pawłowski, Krzysztof and Rezeli, Melinda and Miharada, Kenichi and Gil, Jeovanis and Eriksson, Jonatan and Appelqvist, Roger and Miliotis, Tasso and Baldetorp, Bo and Ingvar, Christian and Olsson, Håkan and Lundgren, Lotta and Horvatovich, Peter and Welinder, Charlotte and Wieslander, Elisabet and Kwon, Ho Jeong and Malm, Johan and Nemeth, Istvan Balazs and Jönsson, Göran and Fenyö, David and Sanchez, Aniel and Marko-Varga, György},
  issn         = {2072-6694},
  language     = {eng},
  number       = {12},
  publisher    = {Multidisciplinary Digital Publishing Institute (MDPI)},
  series       = {Cancers},
  title        = {The hidden story of heterogeneous B-raf V600E mutation quantitative protein expression in metastatic melanoma—association with clinical outcome and tumor phenotypes},
  url          = {http://dx.doi.org/10.3390/cancers11121981},
  doi          = {10.3390/cancers11121981},
  volume       = {11},
  year         = {2019},
}