title: Mutant IDH1 confers an in vivo growth in a melanoma cell line with BRAF mutation.
abstract: Melanoma is the most deadly tumor of the skin, and systemic therapies for the advanced stage are still limited. Recent genetic analyses have revealed the molecular diversity of melanoma and potential therapeutic targets. By screening a cohort of 142 primary nonepithelial tumors, we discovered that about 10% of melanoma cases (4/39) harbored an IDH1 or IDH2 mutation. These mutations were found to coexist with BRAF or KIT mutation, and all IDH1 mutations were detected in metastatic lesions. BRAF-mutated melanoma cells, additionally expressing the cancer-related IDH1 mutant, acquired increased colony-forming and in vivo growth activities and showed enhanced activation of the MAPK and STAT3 pathways. Genome-wide gene expression profiling demonstrated that mutant IDH1 affected the expression of a set of genes. Especially, it caused the induction of growth-related transcriptional regulators (Jun, N-myc, Atf3) and the reduction of Rassf1 and two dehydrogenase genes (Dhrs1 and Adh5), which may be involved in the carcinogenesis of IDH1-mutated tumors. Our analyses demonstrate that IDH1 mutation works with other oncogenic mutations and could contribute to the metastasis in melanoma.
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. tashibat@ncc.go.jp
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Akiko
authors.initials: A
authors.lastname: Kokubu
authors.forename: Masashi
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sasajima
authors.forename: Naoya
authors.initials: N
authors.lastname: Yamazaki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050505:Mutant Proteins; D017382:Reactive Oxygen Species; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf