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

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., 9-Dec-2019, In : Cancers. 11, 12

Research output: Contribution to journalArticleAcademicpeer-review

  • Lazaro Hiram Betancourt
  • A Marcell Szasz
  • Magdalena Kuras
  • Jimmy Rodriguez Murillo
  • Yutaka Sugihara
  • Indira Pla
  • Zsolt Horvath
  • Krzysztof Pawłowski
  • Melinda Rezeli
  • Kenichi Miharada
  • Jeovanis Gil
  • Jonatan Eriksson
  • Roger Appelqvist
  • Tasso Miliotis
  • Bo Baldetorp
  • Christian Ingvar
  • Håkan Olsson
  • Lotta Lundgren
  • Peter Horvatovich
  • Charlotte Welinder
  • Elisabet Wieslander
  • Ho Jeong Kwon
  • Johan Malm
  • Istvan Balazs Nemeth
  • Göran Jönsson
  • David Fenyö
  • Aniel Sanchez
  • György Marko-Varga

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.

Original languageEnglish
Issue number12
Publication statusPublished - 9-Dec-2019

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