TY - JOUR
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
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/12
Y1 - 2019/12
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
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U2 - 10.3390/cancers11121981
DO - 10.3390/cancers11121981
M3 - Article
C2 - 31835364
AN - SCOPUS:85076532893
SN - 2072-6694
VL - 11
JO - Cancers
JF - Cancers
IS - 12
M1 - 1981
ER -