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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

1
Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical, Engineering, Lund University, BMC D13, 221 84 Lund, Sweden
2
Cancer Center, Semmelweis University, Budapest 1083, Hungary
3
Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, 205 02 Malmö, Sweden
4
Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17 177 Stockholm, Sweden
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Department of Biochemistry and Microbiology, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
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Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, Sölvegatan 17, 221 84 Lund, Sweden
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Translational Science, Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, 431 50 Gothenburg, Sweden
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Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 221 85 Lund, Sweden
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Department of Surgery, Clinical Sciences, Lund University, Skåne University Hospital, 222 42 Lund, Sweden
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Department of Analytical Biochemistry, Faculty of Science and Engineering, University of Groningen, 9712 CP Groningen, The Netherlands
11
Department of Biotechnology, Yonsei University, Seoul 03722, Korea
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Department of Dermatology and Allergology, University of Szeged, H-6720 Szeged, Hungary
13
Institute for Systems Genetics, NYU School of Medicine, 550 1st Ave, New York, NY 10016, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this paper as first authors.
These authors contributed equally to this paper as senior authors.
Cancers 2019, 11(12), 1981; https://doi.org/10.3390/cancers11121981
Received: 30 October 2019 / Revised: 23 November 2019 / Accepted: 3 December 2019 / Published: 9 December 2019
(This article belongs to the Special Issue Advanced Melanoma)
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. View Full-Text
Keywords: malignant melanoma; BRAF V600E mutation; proteomics; mass spectrometry genetics; heterogeneity; prognosis malignant melanoma; BRAF V600E mutation; proteomics; mass spectrometry genetics; heterogeneity; prognosis
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Betancourt, L.H.; Szasz, A.M.; Kuras, M.; Rodriguez Murillo, J.; Sugihara, Y.; Pla, I.; Horvath, Z.; Pawłowski, K.; Rezeli, M.; Miharada, K.; Gil, J.; Eriksson, J.; Appelqvist, R.; Miliotis, T.; Baldetorp, B.; Ingvar, C.; Olsson, H.; Lundgren, L.; Horvatovich, P.; Welinder, C.; Wieslander, E.; Kwon, H.J.; Malm, J.; Nemeth, I.B.; Jönsson, G.; Fenyö, D.; Sanchez, A.; Marko-Varga, G. The Hidden Story of Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma—Association with Clinical Outcome and Tumor Phenotypes. Cancers 2019, 11, 1981.

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