Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 30 October 2019 / Approved: 31 October 2019 / Online: 31 October 2019 (10:36:32 CET)

A peer-reviewed article of this Preprint also exists.

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. 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.

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 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.

Keywords

malignant melanoma; BRAF V600E mutation; proteomics; mass spectrometry genetics; heterogeneity; prognosis

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.