title: Activation of the mitogen-activated protein kinase pathway in malignant melanoma can occur independently of the BRAF T1799A mutation.
abstract: BRAF exon 15 mutations have been identified in a large proportion of malignant melanomas, melanoma metastases and melanocytic nevi. Mutated BRAF is one of the potential activators of the mitogen-activated protein kinase (MAPK) signaling pathway by phosphorylating ERK (extracellular signal-regulated kinase). We therefore analyzed the correlation of BRAF V600E and ERK-activation in 20 malignant melanomas and 21 subsequently evolved, paired metastases of the same donor by BRAF exon 15 DNA sequencing and phospho-specific immunohistochemistry for ERK. Phospho-ERK expression was present in 84% of primary melanomas and in all 19 metastases analyzed. In contrast, BRAF mutational status was concordant in only 12/20 pairs (60%) of the primary melanoma and metastasis of the same patient. Surprisingly, the BRAF mutation did not correlate with pERK expression. As even single tumors showed heterogeneous staining for pERK, we used laser-capture microdissection to study BRAF V600E status in pERK positive and pERK negative cells separately. Even on the single cell level ERK activation did not correlate with the BRAF mutation. Our results demonstrate that, in melanomas, activation of the MAPK pathway can occur through signaling pathways operating independently of BRAF T1799A.
authors.affiliation: Department of Dermatology, University of Tuebingen, Liebermeisterstr. 25, 72076 Tübingen, Germany. amir.yazdi@unil.ch
authors.forename: Amir S
authors.initials: AS
authors.lastname: Yazdi
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
authors.forename: Christian A
authors.initials: CA
authors.lastname: Sander
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
mesh_terms: D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000556:secondary; D042282:Microdissection; D016612:Paraffin Embedding; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases