title: Constitutive activation of the mitogen-activated protein kinase signaling pathway in acral melanomas.
abstract: One of the most attractive clinical targets for melanoma is the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, we examined MAPK signaling activation in a total of 28 acral melanoma samples, consisting of 13 primary tumors and 15 metastases. In line with the previous reports, NRAS/BRAF mutations were rare; only one metastatic tumor had an NRAS E61R mutation, and one primary tumor and two metastases harbored BRAF V599E mutations. Western blot analyses, however, revealed phosphorylated extracellular signal-regulated kinase (ERK)1/2 proteins in 11 of 14 (78.5%) of the acral melanoma tumors. Furthermore, fluorescence in situ hybridization analyses revealed the prominent amplification of the cyclin D1 (CCND1) gene, which is an important down-stream effecter of the MAPK pathway, in 5 of 21 (23.8%) tumors examined. Interestingly, two of three tumors that were negative for phosphorylated ERK proteins according to western blot harbored CCND1 amplifications, suggesting that the increased gene dosage of CCND1 may exert effects similar to phosphorylated ERK proteins in cell growth. We conclude that, despite the low frequency of BRAF/NRAS mutations, the MAPK signaling pathway is constitutively activated in the majority of acral melanomas. This provides a rational basis to include acral melanomas into the clinical trials with MAPK inhibitors.
authors.affiliation: Department of Dermatology, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto, Japan. mtderm@hotmail.com
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Goto
authors.forename: Nami
authors.initials: N
authors.lastname: Ichii
authors.forename: Maki
authors.initials: M
authors.lastname: Yamaura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koga
authors.forename: Akihide
authors.initials: A
authors.lastname: Fujimoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Saida
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019938:Cyclin D1 / Q000235:genetics; D005260:Female; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000556:secondary; D008875:Middle Aged; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D019938:Cyclin D1; D048493:Proto-Oncogene Proteins B-raf