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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T1 - The hidden story of heterogeneous B-raf V600E mutation quantitative protein expression in metastatic melanoma—association with clinical outcome and tumor phenotypes

AU - Betancourt, Lazaro Hiram

AU - Szasz, A. Marcell

AU - Kuras, Magdalena

AU - Murillo, Jimmy Rodriguez

AU - Sugihara, Yutaka

AU - Pla, Indira

AU - Horvath, Zsolt

AU - Pawłowski, Krzysztof

AU - Rezeli, Melinda

AU - Miharada, Kenichi

AU - Gil, Jeovanis

AU - Eriksson, Jonatan

AU - Appelqvist, Roger

AU - Miliotis, Tasso

AU - Baldetorp, Bo

AU - Ingvar, Christian

AU - Olsson, Håkan

AU - Lundgren, Lotta

AU - Horvatovich, Peter

AU - Welinder, Charlotte

AU - Wieslander, Elisabet

AU - Kwon, Ho Jeong

AU - Malm, Johan

AU - Nemeth, Istvan Balazs

AU - Jönsson, Göran

AU - Fenyö, David

AU - Sanchez, Aniel

AU - Marko-Varga, György

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - BRAF V600E mutation

KW - Heterogeneity

KW - Malignant melanoma

KW - Mass spectrometry genetics

KW - Prognosis

KW - Proteomics

U2 - 10.3390/cancers11121981

DO - 10.3390/cancers11121981

M3 - Article

C2 - 31835364

AN - SCOPUS:85076532893

VL - 11

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 12

M1 - 1981

ER -