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• W2074200851 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. 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. Melanoma is the most malignant tumor of the skin, and the median survival rate of patients with metastatic tumors is less than 1 year.1Tsao H. Atkins M.B. Sober A.J. Management of cutaneous melanoma.N Engl J Med. 2004; 351: 998-1012Crossref PubMed Scopus (686) Google Scholar Although the incidence of melanoma has been increasing around the world, systemic therapies for the advanced stage are still limited.2Verma S. Quirt I. McCready D. Bak K. Charette M. Iscoe N. Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma.Cancer. 2006; 106: 1431-1442Crossref PubMed Scopus (116) Google Scholar Recent studies have provided a clearer picture of the molecular events leading to melanoma development and progression.3Kuphal S. Bosserhoff A. Recent progress in understanding the pathology of malignant melanoma.J Pathol. 2009; 219: 400-409Crossref PubMed Scopus (56) Google Scholar, 4Curtin J.A. Fridlyand J. Kageshita T. Patel H.N. Busam K.J. Kutzner H. Cho K.H. Aiba S. Bröcker E.B. LeBoit P.E. Pinkel D. Bastian B.C. Distinct sets of genetic alterations in melanoma.N Engl J Med. 2005; 353: 2135-2147Crossref PubMed Scopus (2126) Google Scholar Since the identification of prevalent activating mutations of BRAF kinase,5Davies H. Bignell G.R. Cox C. Stephens P. Edkins S. Clegg S. Teague J. Woffendin H. Garnett M.J. Bottomley W. Davis N. Dicks E. Ewing R. Floyd Y. Gray K. Hall S. Hawes R. Hughes J. Kosmidou V. Menzies A. Mould C. Parker A. Stevens C. Watt S. Hooper S. Wilson R. Jayatilake H. Gusterson B.A. Cooper C. Shipley J. Hargrave D. Pritchard-Jones K. Maitland N. Chenevix-Trench G. Riggins G.J. Bigner D.D. Palmieri G. Cossu A. Flanagan A. Nicholson A. Ho J.W. Leung S.Y. Yuen S.T. Weber B.L. Seigler H.F. Darrow T.L. Paterson H. Marais R. Marshall C.J. Wooster R. Stratton M.R. Futreal P.A. Mutations of the BRAF gene in human cancer.Nature. 2002; 417: 949-954Crossref PubMed Scopus (8270) Google Scholar further molecular studies have clarified the role of this pathway and others in melanomagenesis.6Singh M. Lin J. Hocker T.L. Tsao H. Genetics of melanoma tumorigenesis.Br J Dermatol. 2008; 158: 15-21Crossref PubMed Scopus (41) Google Scholar Recent genetic investigations have also demonstrated specific genotype–phenotype correlations that would be potentially informative in the context of the molecular subclassification of melanoma and therapeutic target molecules.7Fecher L.A. Cummings S.D. Keefe M.J. Alani R.M. Toward a molecular classification of melanoma.J Clin Oncol. 2007; 25: 1606-1620Crossref PubMed Scopus (198) Google Scholar For example, the c-kit gene mutations have been frequently reported in acral lentiginous/mucosal melanomas and are associated with better responsiveness to the inhibitor, imatinib.8Curtin J.A. Busam K. Pinkel D. Bastian B.C. Somatic activation of KIT in distinct subtypes of melanoma.J Clin Oncol. 2006; 24: 4340-4346Crossref PubMed Scopus (1255) Google Scholar, 9Beadling C. Jacobson-Dunlop E. Hodi F.S. Le C. Warrick A. Patterson J. Town A. Harlow A. Cruz 3rd, F. Azar S. Rubin B.P. Muller S. West R. Heinrich M.C. Corless C.L. KIT gene mutations and copy number in melanoma subtypes.Clin Cancer Res. 2008; 14: 6821-6828Crossref PubMed Scopus (509) Google Scholar, 10Handolias D. Hamilton A.L. Salemi R. Tan A. Moodie K. Kerr L. Dobrovic A. McArthur G.A. Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT.Br J Cancer. 2010; 102: 1219-1223Crossref PubMed Scopus (109) Google Scholar Recently, unbiased whole-exon resequencing analysis of glioblastoma multiforme has revealed recurrent mutation of the two IDH (isocitrate dehydrogenase) isoforms, IDH1 and IDH2.11Parsons D.W. Jones S. Zhang X. Lin J.C. Leary R.J. Angenendt P. Mankoo P. Carter H. Siu I.M. Gallia G.L. Olivi A. McLendon R. Rasheed B.A. Keir S. Nikolskaya T. Nikolsky Y. Busam D.A. Tekleab H. Diaz Jr., L.A. Hartigan J. Smith D.R. Strausberg R.L. Marie S.K. Shinjo S.M. Yan H. Riggins G.J. Bigner D.D. Karchin R. Papadopoulos N. Parmigiani G. Vogelstein B. Velculescu V.E. Kinzler K.W. An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812Crossref PubMed Scopus (4527) Google Scholar Subsequent analysis showed that these mutations are frequent in glioma and associated with better prognosis12Yan H. Parsons D.W. Jin G. McLendon R. Rasheed B.A. Yuan W. Kos I. Batinic-Haberle I. Jones S. Riggins G.J. Friedman H. Friedman A. Reardon D. Herndon J. Kinzler K.W. Velculescu V.E. Vogelstein B. Bigner D.D. IDH1 and IDH2 mutations in gliomas.N Engl J Med. 2009; 360: 765-773Crossref PubMed Scopus (4211) Google Scholar, 13Sanson M. Marie Y. Paris S. Idbaih A. Laffaire J. Ducray F. El Hallani S. Boisselier B. Mokhtari K. Hoang-Xuan K. Delattre J.Y. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas.J Clin Oncol. 2009; 27: 4150-4154Crossref PubMed Scopus (782) Google Scholar; furthermore, they have also been detected in a subset (about 8% to 16%) of acute myeloid leukemia (AML).14Mardis E.R. Ding L. Dooling D.J. Larson D.E. McLellan M.D. Chen K. Koboldt D.C. Fulton R.S. Delehaunty K.D. McGrath S.D. Fulton L.A. Locke D.P. Magrini V.J. Abbott R.M. Vickery T.L. Reed J.S. Robinson J.S. Wylie T. Smith S.M. Carmichael L. Eldred J.M. Harris C.C. Walker J. Peck J.B. Du F. Dukes A.F. Sanderson G.E. Brummett A.M. Clark E. McMichael J.F. Meyer R.J. Schindler J.K. Pohl C.S. Wallis J.W. Shi X. Lin L. Schmidt H. Tang Y. Haipek C. Wiechert M.E. Ivy J.V. Kalicki J. Elliott G. Ries R.E. Payton J.E. Westervelt P. Tomasson M.H. Watson M.A. Baty J. Heath S. Shannon W.D. Nagarajan R. Link D.C. Walter M.J. Graubert T.A. DiPersio J.F. Wilson R.K. Ley T.J. Recurring mutations found by sequencing an acute myeloid leukemia genome.N Engl J Med. 2009; 361: 1058-1066Crossref PubMed Scopus (1800) Google Scholar, 15Chou W.C. Hou H.A. Chen C.Y. Tang J.L. Yao M. Tsay W. Ko B.S. Wu S.J. Huang S.Y. Hsu S.C. Chen Y.C. Huang Y.N. Chang Y.C. Lee F.Y. Liu M.C. Liu C.W. Tseng M.H. Huang C.F. Tien H.F. Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation.Blood. 2010; 115: 2749-2754Crossref PubMed Scopus (173) Google Scholar, 16Abbas S. Lugthart S. Kavelaars F.G. Schelen A. Koenders J. Zeilemaker A. van Putten W.J. Rijneveld A. Löwenberg B. Valk P.J. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value.Blood. 2010; 16: 2122-2126Crossref Scopus (306) Google Scholar, 17Paschka P. Schlenk R.F. Gaidzik V.I. Habdank M. Krönke J. Bullinger L. Späth D. Kayser S. Zucknick M. Götze K. Horst H.A. Germing U. Döhner H. Döhner K. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication.J Clin Oncol. 2010; 28: 3636-3643Crossref PubMed Scopus (649) Google Scholar These enzymes convert isocitrate to α-ketoglutarate (α-KG) with concurrent reduction of NADPH, but IDH1 is localized in the cytosol18Geisbrecht B.V. Gould S.J. The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase.J Biol Chem. 1999; 274: 30527-30533Crossref PubMed Scopus (151) Google Scholar whereas IDH2 is localized in mitochondria.19Nekrutenko A. Hillis D.M. Patton J.C. Bradley R.D. Baker R.J. Cytosolic isocitrate dehydrogenase in humans, mice, and voles and phylogenetic analysis of the enzyme family.Mol Biol Evol. 1998; 15: 1674-1684Crossref PubMed Scopus (66) Google Scholar Mutations of the two genes affect the residues responsible for hydrophilic interactions with the substrate, and have been shown to impair the enzymatic activity, and therefore they are considered to be loss-of-function alleles.12Yan H. Parsons D.W. Jin G. McLendon R. Rasheed B.A. Yuan W. Kos I. Batinic-Haberle I. Jones S. Riggins G.J. Friedman H. Friedman A. Reardon D. Herndon J. Kinzler K.W. Velculescu V.E. Vogelstein B. Bigner D.D. IDH1 and IDH2 mutations in gliomas.N Engl J Med. 2009; 360: 765-773Crossref PubMed Scopus (4211) Google Scholar However, because the mutations are clustered in specific residues and only detected as heterozygous alleles, it could also be hypothesized that they are gain-of-function mutations. Recent milestone studies have revealed that mutant IDH1 or IDH2 acquires a new gain-of-function activity that results in reduction of α-ketoglutarate to 2-hydroxyglutarate (2HG) in glioma and leukemia, suggesting that IDH1/2 mutations could be gain-of-function alterations.20Dang L. White D.W. Gross S. Bennett B.D. Bittinger M.A. Driggers E.M. Fantin V.R. Jang H.G. Jin S. Keenan M.C. Marks K.M. Prins R.M. Ward P.S. Yen K.E. Liau L.M. Rabinowitz J.D. Cantley L.C. Thompson C.B. Vander Heiden M.G. Su S.M. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.Nature. 2009; 462: 739-744Crossref PubMed Scopus (2616) Google Scholar, 21Gross S. Cairns R.A. Minden M.D. Driggers E.M. Bittinger M.A. Jang H.G. Sasaki M. Jin S. Schenkein D.P. Su S.M. Dang L. Fantin V.R. Mak T.W. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations.J Exp Med. 2010; 207: 339-344Crossref PubMed Scopus (598) Google Scholar, 22Ward P.S. Patel J. Wise D.R. Abdel-Wahab O. Bennett B.D. Coller H.A. Cross J.R. Fantin V.R. Hedvat C.V. Perl A.E. Rabinowitz J.D. Carroll M. Su S.M. Sharp K.A. Levine R.L. Thompson C.B. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.Cancer Cell. 2010; 17: 225-234Abstract Full Text Full Text PDF PubMed Scopus (1509) Google Scholar Although accumulation of 2HG is associated with a risk of brain tumors including glioma,23Haliloglu G. Jobard F. Oguz K.K. Anlar B. Akalan N. Coskun T. Sass J.O. Fischer J. Topcu M. L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: neuroimaging findings.Neuropediatrics. 2008; 39: 119-122Crossref PubMed Scopus (50) Google Scholar, 24Aghili M. Zahedi F. Rafiee E. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review.J Neurooncol. 2009; 91: 233-236Crossref PubMed Scopus (132) Google Scholar the significance of such metabolic change in carcinogenesis remains largely unknown. Surgical or autopsied specimens (92 cases of sarcoma, 39 cases of melanoma, and 11 cases of mesothelioma) were obtained from patients who were diagnosed and underwent surgery at the National Cancer Center Hospital, Tokyo, Japan. Tumor cells and corresponding lymphocytes or normal skin tissue were dissected out under a microscope from methanol-fixed paraffin-embedded tissues, and the DNA was extracted. High molecular weight DNA was extracted from 13 melanoma cell lines as described previously.25Furuta J. Nobeyama Y. Umebayashi Y. Otsuka F. Kikuchi K. Ushijima T. Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.Cancer Res. 2006; 66: 6080-6086Crossref PubMed Scopus (141) Google Scholar The study protocol for analysis of clinical samples was approved by the institutional review board of the National Cancer Center. We amplified exon 4 of the IDH1 gene, exon 4 of the IDH2 gene, exon 15 of the BRAF gene, exons 2 and 3 (covering codons 12, 13, and 61) of the NRAS gene, exon 3 of the CTNNB1 gene, and exons 11, 13, and 17 of the KIT gene by PCR using High Fidelity Taq polymerase (Roche Diagnostic, Basel, Switzerland) as described.26Shibata T. Kokubu A. Gotoh M. Ojima H. Ohta T. Yamamoto M. Hirohashi S. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer.Gastroenterology. 2008; 135: 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar The primers used in this study are IDH1-EX4F: 5′-AGAGAATCGTGATGCCACCAACG-3′, IDH1-EX4R: 5′-GCATAATGTTGGCGTCAAATGTGC-3′, IDH2-EX4F: 5′-ACATGCAAAATCACATTATTGCC-3′, IDH2-EX4R: 5′-CAAGTTGGAAATTTCTGGGCCATG-3′, BRAF-EX15F: 5′-AAACTCTTCATAATGCTTGCTCTG-3′, BRAF-EX15R: 5′-TAGCCTCAATTCTTACCATCCAC-3′, NRAS-EX2F: 5′-GATGTGGCTCGCCAATTAACCCTG-3′, NRAS-EX2R: 5′-GACAAGTGAGAGACAGGATCAGG-3′, NRAS-EX3F: 5′-TTACCCTCCACACCCCCAGGATTC-3′, NRAS-EX3R: 5′-AATGCTCCTAGTACCTGTAGAGG-3′, KIT-EX11F: 5′-CCAGAGTGCTCTAATGACTGAGAC-3′, KIT-EX11R: 5′-AAAGGTGACATGGAAAGCCCCTG-3′, KIT-EX13F: 5′-AGATGCTCAAGCGTAAGTTCCTG-3′, KIT-EX13R: 5′-AATAAAAGGCAGCTTGGACACGGC-3′, KIT-EX17F: 5′-GGTTTTCTTTTCTCCTCCAACCT-3′, KIT-EX17R: 5′-GTGATATCCCTAGACAGGATTTAC-3′, CTNNB1-EX3F: 5′-TATAGCTGATTTGATGGAGTTGG-3′, CTNNB1-EX3R: 5′-GCTACTTGTTCTTGAGTGAAGGAC-3′. All PCR products were purified (QIAquick PCR purification kit; QIAGEN, Hamburg, Germany) and analyzed by sequencing (Big Dye sequencing kit; Applied Biosystems, Carlsbad, CA). FLAG-tagged IDH1 full-length cDNA was amplified from human normal liver cDNA using reverse transcription (RT)-PCR and subcloned into a mammalian expression plasmid (Invitrogen, Carlsbad, CA). The R132H mutant was generated by site-directed mutagenesis (Quickchange; Stratagene, Santa Clara, CA). All plasmids were validated by sequencing. G361 cells were obtained from Japanese Collection of Research Bioresources (Sennan-shi, Japan) and maintained in DMEM supplemented with 10% fetal bovine serum. Linearized plasmid was transfected by lipofectamine (Invitrogen), and stable clones were isolated after Zeocin (Invitrogen) selection. Cell proliferation was measured using the 96-well plate format by MTS assay using Cell Titer 96 AQueous One Solution Reagent (Promega, Madison, WI).26Shibata T. Kokubu A. Gotoh M. Ojima H. Ohta T. Yamamoto M. Hirohashi S. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer.Gastroenterology. 2008; 135: 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar Colony formation assay and migration assay were performed as described.27Shibata T. Kokubu A. Miyamoto M. Hosoda F. Gotoh M. Tsuta K. Asamura H. Matsuno Y. Kondo T. Imoto I. Inazawa J. Hirohashi S. DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung.Oncogene. 2010; 29: 4671-4681Crossref PubMed Scopus (56) Google Scholar To measure ROS accumulation, cells were stained with 5- (and-6)-chloromethyl-2,7-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA) (Molecular Probes, Eugene, OR), and fluorescence-activated cell sorting (FACS) analysis was performed using FACScalibur (BD Biosciences, San Jose, CA) as instructed by the manufacturer. For assessment of in vivo tumorigenicity, 1 × 106 cells were subcutaneously transplanted into the trunks of nude mice. After 12 weeks, the mice were sacrificed, and the number of subcutaneous tumors as well as metastasis in other organs was examined. The mice were kept at the Animal Care and Use Facilities of the National Cancer Center under specific pathogen-free conditions, and all experiments were approved by the institutional Animal Care and Ethics Committee. For protein extraction, we used a slightly modified buffer (10 mmol/L Tris-HCl [pH 7.5], 175 mmol/L NaCl, 5 mmol/L EDTA, 0.5% Triton-X, 0.5% NP-40) with a proteinase inhibitor cocktail (Roche), and the immunoblotting procedure was preformed as described previously.26Shibata T. Kokubu A. Gotoh M. Ojima H. Ohta T. Yamamoto M. Hirohashi S. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer.Gastroenterology. 2008; 135: 1358-1368Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar The antibodies used in this study are anti-FLAG peptide (clone M2; Sigma-Aldrich, St. Louis, MO), anti-MAPK, phospho-MAPK (pT202/pY204), AKT, phospho-AKT (pS473), phospho-STAT3 (pY705), p70S6K, phospho-p70S6K (pT389) antibodies (Cell Signaling Technologies, Danvers, MA), and anti-STAT3 antibody (BD Biosciences). From subconfluent G361 clones, total RNA was extracted using an RNAeasy kit (QIAGEN). Ten micrograms of total RNA was reverse-transcribed by MMLV-RT, and a Cy3-labeled cRNA probe was synthesized using T7 RNA polymerase and hybridized with a microarray covering the whole human genome (Whole Human Genome Oligo Microarray, G4112F; Agilent Technologies, Santa Clara, CA). All sample were analyzed in duplicate. After washing, the microarray was scanned by the DNA microarray scanner (Agilent Technologies). Data were normalized and statistical significance was measured by t-test with multiple testing correction (Benjamini and Hochberg false discovery rate) using GeneSpring software (Agilent Technologies).27Shibata T. Kokubu A. Miyamoto M. Hosoda F. Gotoh M. Tsuta K. Asamura H. Matsuno Y. Kondo T. Imoto I. Inazawa J. Hirohashi S. DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung.Oncogene. 2010; 29: 4671-4681Crossref PubMed Scopus (56) Google Scholar Quantitative RT-PCR was performed in triplicate and evaluated using universal probes for each amplicon and the LightCycler system (Roche). Primers designed by ProbeFinder (Version 2.45; Roche). The relative expression of each gene was determined by comparison with that of GAPDH. Since previous mutation analyses have reported that IDH1 mutation is rare in epithelial cancers in comparison to glioma and leukemia,28Bleeker F.E. Lamba S. Leenstra S. Troost D. Hulsebos T. Vandertop W.P. Frattini M. Molinari F. Knowles M. Cerrato A. Rodolfo M. Scarpa A. Felicioni L. Buttitta F. Malatesta S. Marchetti A. Bardelli A. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors.Hum Mutat. 2009; 30: 7-11Crossref PubMed Scopus (336) Google Scholar, 29Kang M.R. Kim M.S. Oh J.E. Kim Y.R. Song S.Y. Seo S.I. Lee J.Y. Yoo N.J. Lee S.H. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers.Int J Cancer. 2009; 125: 353-355Crossref PubMed Scopus (268) Google Scholar we searched for the IDH1 gene mutation in a cohort of primary tumors of nonepithelial origin (92 sarcomas, 39 melanomas, and 11 malignant mesotheliomas). Our melanoma cohort included 17 metastatic cases. After screening these 142 tumors, we found 2 melanoma cases harboring heterozygous IDH1 mutation (R132C and R132H, 2/39) (Figure 1 and Table 1). These mutations affected exactly the same residue as that reported for glioma and AML.11Parsons D.W. Jones S. Zhang X. Lin J.C. Leary R.J. Angenendt P. Mankoo P. Carter H. Siu I.M. Gallia G.L. Olivi A. McLendon R. Rasheed B.A. Keir S. Nikolskaya T. Nikolsky Y. Busam D.A. Tekleab H. Diaz Jr., L.A. Hartigan J. Smith D.R. Strausberg R.L. Marie S.K. Shinjo S.M. Yan H. Riggins G.J. Bigner D.D. Karchin R. Papadopoulos N. Parmigiani G. Vogelstein B. Velculescu V.E. Kinzler K.W. An integrated genomic analysis of human glioblastoma multiforme.Science. 2008; 321: 1807-1812Crossref PubMed Scopus (4527) Google Scholar, 12Yan H. Parsons D.W. Jin G. McLendon R. Rasheed B.A. Yuan W. Kos I. Batinic-Haberle I. Jones S. Riggins G.J. Friedman H. Friedman A. Reardon D. Herndon J. Kinzler K.W. Velculescu V.E. Vogelstein B. Bigner D.D. IDH1 and IDH2 mutations in gliomas.N Engl J Med. 2009; 360: 765-773Crossref PubMed Scopus (4211) Google Scholar, 16Abbas S. Lugthart S. Kavelaars F.G. Schelen A. Koenders J. Zeilemaker A. van Putten W.J. Rijneveld A. Löwenberg B. Valk P.J. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value.Blood. 2010; 16: 2122-2126Crossref Scopus (306) Google Scholar No IDH1 mutation was detected in sarcoma and mesothelioma cases. We then screened IDH2 mutation in the same cohort and found two heterozygous mutations (G171D and P158T) that affected well-conserved residues among species in two MM cases (Figure 1). Especially G171 is located next to the most frequently altered residue (R172), but its mutation in cancer has not been reported previously.12Yan H. Parsons D.W. Jin G. McLendon R. Rasheed B.A. Yuan W. Kos I. Batinic-Haberle I. Jones S. Riggins G.J. Friedman H. Friedman A. Reardon D. Herndon J. Kinzler K.W. Velculescu V.E. Vogelstein B. Bigner D.D. IDH1 and IDH2 mutations in gliomas.N Engl J Med. 2009; 360: 765-773Crossref PubMed Scopus (4211) Google Scholar, 14Mardis E.R. Ding L. Dooling D.J. Larson D.E. McLellan M.D. Chen K. Koboldt D.C. Fulton R.S. Delehaunty K.D. McGrath S.D. Fulton L.A. Locke D.P. Magrini V.J. Abbott R.M. Vickery T.L. Reed J.S. Robinson J.S. Wylie T. Smith S.M. Carmichael L. Eldred J.M. Harris C.C. Walker J. Peck J.B. Du F. Dukes A.F. Sanderson G.E. Brummett A.M. Clark E. McMichael J.F. Meyer R.J. Schindler J.K. Pohl C.S. Wallis J.W. Shi X. Lin L. Schmidt H. Tang Y. Haipek C. Wiechert M.E. Ivy J.V. Kalicki J. Elliott G. Ries R.E. Payton J.E. Westervelt P. Tomasson M.H. Watson M.A. Baty J. Heath S. Shannon W.D. Nagarajan R. Link D.C. Walter M.J. Graubert T.A. DiPersio J.F. Wilson R.K. Ley T.J. Recurring mutations found by sequencing an acute myeloid leukemia genome.N Engl J Med. 2009; 361: 1058-1066Crossref PubMed Scopus (1800) Google Scholar, 15Chou W.C. Hou H.A. Chen C.Y. Tang J.L. Yao M. Tsay W. Ko B.S. Wu S.J. Huang S.Y. Hsu S.C. Chen Y.C. Huang Y.N. Chang Y.C. Lee F.Y. Liu M.C. Liu C.W. Tseng M.H. Huang C.F. Tien H.F. Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation.Blood. 2010; 115: 2749-2754Crossref PubMed Scopus (173) Google Scholar, 16Abbas S. Lugthart S. Kavelaars F.G. Schelen A. Koenders J. Zeilemaker A. van Putten W.J. Rijneveld A. Löwenberg B. Valk P.J. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value.Blood. 2010; 16: 2122-2126Crossref Scopus (306) Google Scholar, 17Paschka P. Schlenk R.F. Gaidzik V.I. Habdank M. Krönke J. Bullinger L. Späth D. Kayser S. Zucknick M. Götze K. Horst H.A. Germing U. Döhner H. Döhner K. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication.J Clin Oncol. 2010; 28: 3636-3643Crossref PubMed Scopus (649) Google Scholar, 28Bleeker F.E. Lamba S. Leenstra S. Troost D. Hulsebos T. Vandertop W.P. Frattini M. Molinari F. Knowles M. Cerrato A. Rodolfo M. Scarpa A. Felicioni L. Buttitta F. Malatesta S. Marchetti A. Bardelli A. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors.Hum Mutat. 2009; 30: 7-11Crossref PubMed Scopus (336) Google Scholar, 29Kang M.R. Kim M.S. Oh J.E. Kim Y.R. Song S.Y. Seo S.I. Lee J.Y. Yoo N.J. Lee S.H. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers.Int J Cancer. 2009; 125: 353-355Crossref PubMed Scopus (268) Google Scholar These IDH1/2 mutations were not detected in the corresponding normal tissues, and in total, we detected four somatic IDH1/2 mutations out of 39 melanoma cases (10.3%). Three out of four IDH1/2 mutations occurred in either mucosal or acral lentiginous subtype, and IDH1 mutation was detected only in metastatic lesions (Table 1).Table 1Clinicopathological and Mutation Profile of Melanoma CasesCasePrimary (P) or metastatis (M) sitePrimary siteSubtypeIDH1IDH2BRAFNRASKITCTNNB1MM-1M, left thighFacendp.R132C, heterop.V600E, heteroMM-27M, liverAnalndp.R132H, heterop.K642E, homoMM-38PAbdomenndp.P158T, heterop.V600E, heteroMM-3PToeNMp.G171D, heteroMM-24M, pancreasFingerALMp.D594N, heteroMM-4PEsophagusndp.V600E, heteroMM-7PSkinALMp.V600E, heteroMM-12PEsophagusndp.V600E, heteroMM-14M, brainForearmndp.V600E, heteroMM-16M, liverSoleALMp.V600E, heteroMM-25M, ndChest wallNMp.V600E, heteroMM-6PSoleALMp.V600E, homop.T41I, heteroMM-23M, LNSkinNMp.V600E, homoMM-32PThighNMp.V600E, homoMM-2PEsophagusndp.Q61H, heteroMM-10M, LNHeadNMp.G12S, heteroMM-15PEsophagusndp.G13R, heteroMM-26PPharyngealndp.Q61H, homoMM-28M, ndShoulderNMp.Q61R, homoMM-31PHeelALMp.G12S, heteroMM-33PSoleALMp.G12S, heteroMM-36PSoleALMp.Q61R, homoMM-20M, LNFingerALMp.K642E, homoMM-22M, LNSkinNMp.N822K, heteroMM-30PSoleALMp.I817F, heteroMM-18M, ndConjunctivandp.T40I, heteroMM-19M, ndSoleALMp.P44L, heteroMM-37PSoleALMMM-39PLegSSMMM-5PFaceALMMM-8PToeALMMM-9M, skinNDndMM-11PRectumndMM-13M, brainThighSSMMM-17M, ndConjunctivandMM-21PAbdomenndMM-29M, ndForearmndMM-34PConjunctivandMM-35PSoleALMClinicopathological (primary or metastasis, primary and metastatic organ site and histological subtype) and mutation (amino acid change and zygosity) data of the analyzed cases are shown.nd, not determined; hetero, heterozygous mutation; homo, homozygous mutation; NM, nodular melanoma; ALM, acral lentigous melanoma; LN, lymph node; SSM, superficial spreading melanoma. Open table in a new tab Clinicopathological (primary or metastasis, primary and metastatic organ site and histological subtype) and mutation (amino acid change and zygosity) data of the analyzed cases are shown. nd, not determined; hetero, heterozygous mutation; homo, homozygous mutation; NM, nodular melanoma; ALM, acral lentigous melanoma; LN, lymph node; SSM, superficial spreading melanoma. We next examined mutations of the melanoma-associated oncogenes (the BRAF, NRAS, KIT, and CTNNB1 genes) in our study cases. In this cohort, we detected 12 BRAF mutations (30.8%), 8 NRAS mutations (20.5%), 4 KIT mutations (10.2%), and 3 CTNNB1 mutations (7.7%) (Table 1). As reported previously,4Curtin J.A. Fridlyand J. Kageshita T. Patel H.N. Busam K.J. Kutzner H. Cho K.H. Aiba S. Bröcker E.B. LeBoit P.E. Pinkel D. Bastian B.C. Distinct sets of genetic alterations in melanoma.N Engl J Med. 2005; 353: 2135-2147Crossref PubMed Scopus (2126) Google Scholar, 8Curtin J.A. Busam K. Pinkel D. Bastian B.C. Somatic activation of KIT in distinct subtypes of melanoma.J Clin Oncol. 2006; 24: 4340-4346Crossref PubMed Scopus (1255) Google Scholar the existence of BRAF, NRAS, and KIT mutations is mutually exclusive, and one case contains both BRAF and CTNNB1 mutations. Among the IDH1/2-mutated cases, two had both BRAF and IDH1 or IDH2 mutations, and one had KIT and IDH1 mutations. We also screened IDH1, IDH2, BRAF, NRAS, and KIT mutations in 13 melanoma cell lines. We observed nine BRAF mutations (9/13, 69.2%) and one NRAS mutation (1/13, 7.7%) in these cell lines, but were unable to detect any IDH1 or IDH2 mutation (data not shown). Previous studies have shown that BRAF mutation occurs at the early stage of melanoma development.30Papp T. Schipper H. Kumar K. Schiffmann D. Zimmermann R. Mutational analysis of the BRAF gene in human congenital and dysplastic melanocytic naevi.Melanoma Res. 2005; 15: 401-407Crossref PubMed Scopus (48) Google Scholar, 31Poynter J.N. Elder J.T. Fullen D.R. Nair R.P. Soengas M.S. Johnson T.M. Redman B. Thomas N.E. Gruber S.B. BRAF and NRAS mutations in melanoma and melanocytic nevi.Melanoma Res. 2006; 16: 267-273Crossref PubMed Scopus (195) Google Scholar Therefore, based on the above genetic analysis, we speculated that IDH mutation confers a growth advantage after acquiring BRAF or KIT mutation. Because the functional significance of I" @default.
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