人脑胶质瘤中IDH1基因突变及DNA甲基化调控与干细胞相关基因表达
摘要
脑胶质瘤是神经系统原发肿瘤中的最常见类型,随着现代医学发展及综合治疗技术的进步,脑胶质瘤的诊断与治疗有了很大提高,但其疗效预后并没有明显改善,因此,积极探索胶质瘤发生发展的分子机制并在肿瘤防治上寻找新的突破仍是当前医学研究的热点。
异柠檬酸脱氢酶1(isocitrate dehydrogenase 1, IDH1)是三羧酸循环关键酶之一,其编码基因突变在胶质瘤中发生频率很高,具有胶质瘤特异性。IDH1基因突变可激活细胞缺氧诱导因子1α(hypoxia-inducible factor 1α, HIF-1α)信号通路,可能是脑胶质瘤发生发展的重要原因。
本课题采用直接测序法检测了24例脑星形细胞胶质瘤患者原发及原位复发肿瘤样本中IDH1的突变分布,发现原发胶质瘤中IDH1基因突变发生率为54.2%,复发胶质瘤中突变分布与原发肿瘤一致。同时检测原复发肿瘤样本中干细胞相关基因OCT4、CD133 mRNA、蛋白及阳性细胞的表达水平,并根据IDH1突变分布和病理级别进行配对分析,结果显示：IDH1突变在原发胶质瘤中可促进干细胞相关基因表达上调；而复发胶质瘤中干细胞相关基因表达上调与IDH1突变似无明显相关。进一步对OCT4、CD133、IDH1的启动子甲基化水平进行BSP克隆测序检测,并分析目标基因甲基化水平与基因表达的相关性,结果提示：DNA低甲基化可上调OCT4、CD133基因表达,可能是复发胶质瘤中干细胞相关基因表达上调的主要原因之一,且部分参与了原发胶质瘤的发生过程；而IDH1启动子在原复发胶质瘤中均没有发生明显DNA甲基化。
本课题初步证明了人脑胶质瘤中IDH1基因突变可促进干细胞相关基因的表达,可能是原发胶质瘤发生的重要机制之一,而DNA低甲基化可上调干细胞相关基因表达,在胶质瘤发生、复发过程中同样也发挥着重要的调控作用。这为进一步理解胶质瘤的发生机制与探索临床治疗新方向提供了部分实验基础。
Glioma is the most common tumor of nervous system. With the development of modern medicine and treatment advances, diagnosis and treatment of glioma had been greatly improved, but its prognosis had not been improved significantly. So the molecular mechanism of the development of glioma and the new breakthroughs in medical research remained a current hot spot.
Isocitrate dehydrogenase(IDH1) was one of the key enzymes in the citric acid cycle, and its'encoding gene mutations frequently in glioma. Further studies showed that IDHl mutations decreased its downstream products of a-ketoglutarate (a-KG), thus activated the HIF signaling pathway and promoted glioma formation.
This issue analysised the relevance and the possible mechanism of IDHl mutation and stem cell-related genes expression of OCT4 and CD133 in 24 cases of primary and corresponding recurrent glioma tumor samples, in order to further understand the carcinogenic mechanism of IDHl mutation in gliomas and to provide new ideas and experiments for glioma stem cells research. The results showed that: IDH1 mutations have significant correlation with increased expression of OCT4 and CD133 in primary glioma; IDHl mutations have no significant correlation with increased expression of OCT4 and CD133 in glioma recurrence process. Then we detected IDH1, OCT4, CD133 promoter methylation by BSP cloning sequencing and analysised the relation of DNA methylation level and gene expression. The results showed:DNA methylation can regulate the gene expression of OCT4 and CD133 in primary gliomas; The promoter DNA methylation level of OCT4 and CD133 declined in recurrent glioma and it may be one of the main reasons of glioma recurrence; there was no obvious DNA methylation of IDH1 promoter region in gliomas.
Taken together, our studies implicate that IDH1 mutations can promote stem cell-related gene expression in primary human glioma, and DNA methylation also play an important role in human glioma occurrence and recurrence. And our studies contribute to understand the pathogenesis of glioma and provided some experimental basis for new direction to explore the clinical treatment of glioma.
异柠檬酸脱氢酶1(isocitrate dehydrogenase 1, IDH1)是三羧酸循环关键酶之一,其编码基因突变在胶质瘤中发生频率很高,具有胶质瘤特异性。IDH1基因突变可激活细胞缺氧诱导因子1α(hypoxia-inducible factor 1α, HIF-1α)信号通路,可能是脑胶质瘤发生发展的重要原因。
本课题采用直接测序法检测了24例脑星形细胞胶质瘤患者原发及原位复发肿瘤样本中IDH1的突变分布,发现原发胶质瘤中IDH1基因突变发生率为54.2%,复发胶质瘤中突变分布与原发肿瘤一致。同时检测原复发肿瘤样本中干细胞相关基因OCT4、CD133 mRNA、蛋白及阳性细胞的表达水平,并根据IDH1突变分布和病理级别进行配对分析,结果显示：IDH1突变在原发胶质瘤中可促进干细胞相关基因表达上调；而复发胶质瘤中干细胞相关基因表达上调与IDH1突变似无明显相关。进一步对OCT4、CD133、IDH1的启动子甲基化水平进行BSP克隆测序检测,并分析目标基因甲基化水平与基因表达的相关性,结果提示：DNA低甲基化可上调OCT4、CD133基因表达,可能是复发胶质瘤中干细胞相关基因表达上调的主要原因之一,且部分参与了原发胶质瘤的发生过程；而IDH1启动子在原复发胶质瘤中均没有发生明显DNA甲基化。
本课题初步证明了人脑胶质瘤中IDH1基因突变可促进干细胞相关基因的表达,可能是原发胶质瘤发生的重要机制之一,而DNA低甲基化可上调干细胞相关基因表达,在胶质瘤发生、复发过程中同样也发挥着重要的调控作用。这为进一步理解胶质瘤的发生机制与探索临床治疗新方向提供了部分实验基础。
Glioma is the most common tumor of nervous system. With the development of modern medicine and treatment advances, diagnosis and treatment of glioma had been greatly improved, but its prognosis had not been improved significantly. So the molecular mechanism of the development of glioma and the new breakthroughs in medical research remained a current hot spot.
Isocitrate dehydrogenase(IDH1) was one of the key enzymes in the citric acid cycle, and its'encoding gene mutations frequently in glioma. Further studies showed that IDHl mutations decreased its downstream products of a-ketoglutarate (a-KG), thus activated the HIF signaling pathway and promoted glioma formation.
This issue analysised the relevance and the possible mechanism of IDHl mutation and stem cell-related genes expression of OCT4 and CD133 in 24 cases of primary and corresponding recurrent glioma tumor samples, in order to further understand the carcinogenic mechanism of IDHl mutation in gliomas and to provide new ideas and experiments for glioma stem cells research. The results showed that: IDH1 mutations have significant correlation with increased expression of OCT4 and CD133 in primary glioma; IDHl mutations have no significant correlation with increased expression of OCT4 and CD133 in glioma recurrence process. Then we detected IDH1, OCT4, CD133 promoter methylation by BSP cloning sequencing and analysised the relation of DNA methylation level and gene expression. The results showed:DNA methylation can regulate the gene expression of OCT4 and CD133 in primary gliomas; The promoter DNA methylation level of OCT4 and CD133 declined in recurrent glioma and it may be one of the main reasons of glioma recurrence; there was no obvious DNA methylation of IDH1 promoter region in gliomas.
Taken together, our studies implicate that IDH1 mutations can promote stem cell-related gene expression in primary human glioma, and DNA methylation also play an important role in human glioma occurrence and recurrence. And our studies contribute to understand the pathogenesis of glioma and provided some experimental basis for new direction to explore the clinical treatment of glioma.
引文
[1]Louis DN, Ohgaki H, Wiestler OD,Cavenee WK, et al. WHO classifcation of tumours of the central nervous system.4th ed. Lyon, France:IARC Press,2007.
[2]Stupp R, Mason WP, van den Bent MJ,et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
[3]Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008; 359: 492-507.[Erratum, N Engl J Med 2008;359:877.]
[4]D.W.Parsons et al.An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science 321,1807 (2008).
[5]Balss J, Meyer J, Mueller W, et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 2008;116:597-602.
[6]Bleeker FE, Lamba S, Leenstra S, et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 2009; 30:7-11.
[7]Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360:765-773.
[8]Korshunov A, Meyer J, Capper D, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 2009; 118:401-405.
[9]Mi Ran Kang, Min Sung Kim, Ji Eun Oh, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int. J. Cancer 2009; 125:353-355.
[10]Yukihiko Sonoda, Toshihiro Kumabe, Taigen Nakamura, et al. Analysis of IDH1 and IDH2 mutations in Japanes glioma patients. Cancer Sci 2009; 100: 1996-1998.
[11]Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 2009, 27(25):4150-4.
[12]Christian Hartmann, Jochen Meyer, Jo'rg Balss, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age:a study of 1,010 diffuse gliomas. Acta Neuropathol 2009,118:469-474.
[13]Koichi Ichimura, Danita M. Pearson, Sylvia Kocialkowski, et al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro-Oncology 2009,11:341-347.
[14]Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007;170:1445-53.
[15]Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics,biology, and paths to treatment. Genes Dev 2007;21:2683-710.
[16]Weber RG, Sabel M, Reifenberger J, et al. Characterization of genomic alterations associated with glioma progression by comparative genomic hybridization. Oncogene 1996; 13:983-94.
[17]Bigner SH, Matthews MR, Rasheed BK, et al. Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization. Am J Pathol 1999;155:375-86.
[18]Jansen, G. A., S. J. Mihalik, P. A. Watkins, H. W. Moser, C. Jakobs, S. Denis, and R. J. Wanders. Phytanoyl-CoA hydroxylase is present in human liver, located in peroxisomes, and deficient in Zellweger syndrome:direct, unequivocal evidence for the new, revised pathway of phytanic acid alpha-oxidation in humans. Biochem. Biophys. Res. Commun 1996,229: 205-210.
[19]Mihalik, S. J., A. M. Rainville, and P. A. Watkins. Phytanic acid alpha-oxidation in rat liver peroxisomes. Production of alphahy-droxyphytanoyl-CoA and formate is enhanced by dioxygenase cofactors. Eur. J. Biochem 1995,232: 545-551.
[20]Croes, K., M. Casteels, E. De Hoffmann, G. P. Mannaerts, and P. P. Van Veldhoven. Alpha-oxidation of 3-methyl-substituted fatty acids in rat liver. Production of formic acid instead of CO2, cofactor requirements, subcellular localization and formation of a 2-hydroxy-3-methylacyl-CoA intermediate. Eur. J. Biochem 1996,240:674-683.
[21]Verhoeven, N. M., and C. Jakobs. Human metabolism of phytanic acid and pristanic acid. Prog. Lipid Res 2001,40:453-466.
[22]Lee, S. M., H. J. Koh, D. C. Park, B. J. Song, T. L. Huh, and J. W. Park. Cytosolic NADP-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic. Biol. Med 2002,32:1185-1196.
[23]Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 2009;324:261-265.
[24]Birner P, SchindlM, McNultyW. Hypoxia-inducible factor-1α is a marker for an unfavorable p rognosis in early stage invasive cervical cancer[J]. Cancer Res,2000,60:4693-4696.
[25]KaurB, Khwaja FW, Severson EA, et al. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis [J]. Neuro-Oncol,2005,7 (2):134-153.
[26]Zhong H, Semenza GL, Simons JW, et al. Up-regulation of hypoxia-inducible factor 1alpha is an early event in p rostate carcinogenesis[J]. CancerDetect Prev,2004,28 (2):88-93.
[27]Adelman D. M., Gertsrnstein M., Nagy A., Simon M.C., andMaltepe E. Placental cell fates are regulated in vivo by H IF-mediated hypoxia responses. Gene and Development 2000,14,3191-3203.
[28]Tomita S., Ueno M., Sakamoto M., Kitahama Y., UekiM., Maekawa N., et al. Defective brain development in mice lacking the Hif-1α gene in neural cells.Mol. Cell. Biol 2003,23:6739-6749.
[29]Singh SK, Clarkei D, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors [J]. Cancer Res,2003,63(18):5821-5828.
[30]Singh SK, Clarkei D, Hide T, et al. Cancer stem cells in nervous system tumors [J]. Oncogene,2004,23(43):7267-7273.
[31]Marx J. Mutant stem cells may seed cancer [J]. Science,2003,301(5638):1308-1310.
[32]Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma [J]. Cancer Res,2004,64(19):7011-7021.
[33]Hemmati H D, Nakano I, Lazareff J A, et al. Cancerous stem cells can arise from pediatric brain tumors [J]. Proc Nat Acad Sci USA,2003,100(25):15178-15183.
[34]Scholer HR, Ruppert S, SuzukiN, et al. New type of POU domain in germ Iine2specific p rotein Oct24 [J]. Nature,1990,344 (6265)
[35]Pesce M, Sch€oler HR. Oct-4:Gatekeeper in the beginnings of mammalian development. Stem Cells 2001,19:271-278.
[36]Monk M, Holding C. Human embryonic genes re-expressed in cancer cells. Oncogene 2001,20:8085-8091.
[37]Atlasi Y, Mowla SJ, Ziaee SA, Bahrami AR. OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. Int J Cancer 2007,120:1598-1602.
[38]Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE. Oct4 expression in adult human stem cells:Evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis 2005,26:495-502.
[39]Webster JD, Yuzbasiyan-Gurkan V, Trosko JE, Chang CC, Kiupel M. Expression of the embryonic transcription factor Oct4 in canine neoplasms:A potential marker for stem cell subpopulations in neoplasia. Vet Pathol 2007, 44:893-900.
[40]Zhanghui Du,Deyong Jia, Shangming Liu, et al. Oct4 is Expressed in Human Gliomas and Promotes Colony Formation in Glioma Cells. GLIA 2009,57:724-733.
[41]Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma [J]. Cancer Res,2004,64(19):7011-7021.
[42]Kang MK, Kang SK. Tumorigenesis of chemotherapeutic drug2resistant cancer stem2like cells in brain glioma [J].Stem Cells Dev,2007,16 (5):837.
[43]Gonzalez J, Gilbert MR. Treatment of astrocytomas. Curr Opin Neurol. 2005; 18:632-638.
[44]Hentschel SJ, Lang FF. Current surgical management of glioblastoma. Cancer J. 2003;9:113-125.
[45]Olson JJ. Neurosurgical advances in the treatment of brain tumors. Curr Oncol Rep.2000;2:434-437.
[46]Harbaugh KS, Black PM. Strategies in the surgical management of malignant gliomas. Semin Surg Oncol.1998;14:26-33.
[47]Toms SA, Ferson DZ, Sawaya R. Basic surgical techniques in the resection of malignant gliomas. J Neuro Oncol.1999;42:215-226.
[48]Wallner KE, Galicich JH, Krol G, Arbit E,Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys.1989;16:1405-1409.
[49]Burger PC, Dubois PJ, Schold SC Jr, et al. Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg.1983;58:159-169.
[50]Gaspar LE, Fisher BJ, Macdonald DR, et al. Supratentorial malignant glioma: patterns of recurrence and implications for external beam local treatment. Int J Radiat Oncol Biol Phys.1992;24:55-57.
[51]Mitchell P, Ellison DW, Mendelow AD. Surgery for malignant gliomas: mechanistic reasoning and slippery statistics. Lancet Neurol.2005;4:413-422.
[52]Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ. Imagingbased stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg.1987;66:865-874.
[53]Brower V. Search and destroy:recent research exploits adult stem cells' attraction to cancer. J Natl Cancer Inst.2005;97:414-416.
[54]Burger PC, Heinz ER, Shibata T, Kleihues P. Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg. 1988;68:698-704.
[55]Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration:invasion of malignant gliomas and implications for treatment. J Clin Oncol. 2003;21:1624-1636.
[56]Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell.2007; 11:69-82.
[57]Yang ZJ. Wechsler-Reya RJ. et al. where they live:targeting the cancer stem cell niche. Cancer Cell.2007;11:3-5.
[58]Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis:epigenetics joins genetics. Trends Genet,2000,16:168-1741.
[59]Ellis L, Atadja PW, Johnstone RW1 Epigenetics in cancer:targeting chromatin modifications [J] 1 Mol Cancer Ther,2009,6 (8):1409214201.
[60]EhrichM, Turner J, Gibbs P, et al.. Cytosine methylation profiling of cancer cell lines[J]. Proc. Nat. Acad. Sci. USA,2008,105 (12):4844-4849
[61]Herman J G, Baylin S B. Gene silencing in cancer in association with p romoter hypermethylation [J]. N. Eng. J. Med.,2003,349 (21):2042-2054.
[62]Yuasa Y. DNA methylation in cancer and ageing [J]. Meeh Age ing Dev,2002, 123 (12):1649-1654.
[63]Jones PA, Laird PW. Cancer epigenetics comes of age Nat Genet 1999; 21:163-71.
[64]Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene 2001; 20:3139-31551.
[65]Yu J, Zhang H, Gu J, et al. Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma [J]. BMC Cancer,2004,4:65.
[66]Kimt Y, Zhong S, Fields CR, et al. Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma [J].Cancer Res,2006,66(15):7490-7501.
[67]Alaminson M, Davalos V, Ropero S, et al. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma [J]. Cancer Res, 2005,65(7):2565-2571.
[68]Maegawa S, Itaba N, Otsuka S, et al. Coordinate downregulation of a novel imprinted transcript ITUP1 with PEG3 in glioma cell lines [J]. DNA Res,2004, 11(1):37-49.
[69]Gao Y, Guan M, Su B, et al. Hypermethylation of the RASSF1A gene in gliomas [J]. Clin Chim Acta,2004,349 (1-2):173-179.
[70]Alonso ME, Bello MJ, Gonzalez-Gomez P, et al. Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas [J]. Cancer Genet Cytogenet,2003,144(2):134-142.
[71]Horiguchi K, Tomizawa Y, Tosaka M, et al. Epigenetic inactivation of RASSF1A candidate tumor suppressor gene at 3p21.3 in brain tumors [J]. Oncogene,2003,22(49):7862-7865.
[72]Hesson L, Bieche I, Krex D, et al. Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas [J]. Oncogene,2004,23 (13):2408-2419.
[73]Balana C, Ramirez JL, Taron M, et al. O6-methylguanine-DNA methyltransferase methylation in serum and tumor DNA predicts r esponse to 1, 3-bis (2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme [J]. Clin Cancer Res,2003,9(4):1461-1468.
[74]Cankovic M, Mikkelsen T, Rosenblum ML, et al. A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin-fixed paraffin-embedded tissue [J]. Lab Invest,2007, 87(4):392-397.
[75]Pazm F, Yaya-Tur R, Rojas-Marcos I, et al. CpG island hypermethylation of the DNA repair enzyme methyltrans-ferase predicts response to temozolomide in primary gliomas [J]. Clin Cancer Res,2004,10(15):4933-4938.
[76]Mollemann M, Wolter M, Felsberg J, et al. Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors [J]. Int J Cancer,2005,113(3):379-385.
[77]Gonzalez-Gomezo P, Bello MJ, Arjona D, et al. Promoter hypermethylation of multiple genes in astrocytic gliomas [J]. Int J Oncol,2003,22(3):601-608.
[78]Maxwell JA, Johnson SP, Quinn JA, et al. Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma [J]. Mol Cancer Ther,2006,5(10):2531-2539.
[79]Uhlmann K, Rohde K, Zeller C, et al. Distinct methylation profiles of glioma subtypes [J]. Int J Cancer,2003,106(1):52-59.
[80]Weaver KD, Grossman SA, Herman J G. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma [J]. Cancer Invest,2006,24(1):35-40.
[81]Rosenbaum E, Hoque MO, Cohen Y, et al. Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy [J]. Clin Cancer Res,2005,11(23):8321-8325.
[82]Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide [J]. Clin Cancer Res,2004,10(6):1871-1874.
[83]Robert MF, Morin S, Beaulieu N, et al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells [J]. Net Cenet, 2003,33(1):61-65.
[84]Niwa H. Molecular mechanism to maintain stem cell renewal of ES cells. Cell Struct Funct,2001,26(3):137-48
[85]Ben-Shushan, E., E. Pikarsky, A. Klar, and Y. Bergman. Extinction of Oct-3/4 gene expression in embryonal carcinoma_fibroblast somatic cell hybrids is accompanied by changes in the methylation status, chromatin structure, and transcriptional activity of the Oct-3/4 upstream region. Mol. Cell. Biol 1993, 13:891-901.
[86]Deb-Rinker, P., D. Ly, A. Jezierski, M. Sikorska, and P. R. Walker. Sequential DNA methylation of the Nanog and Oct-4 upstream regions in human NT2 cells during neuronal differentiation. J. Biol. Chem 2005,280:6257-6260.
[87]Feldman, N., A. Gerson, J. Fang, E. Li, Y. Zhang, Y. Shinkai, H. Cedar, and Y. Bergman. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat. Cell Biol,2006(8):188-194.
[88]Gidekel, S., and Y. Bergman. A unique developmental pattern of Oct-3/4 DNA methylation is controlled by acis-demodification element. J. Biol. Chem 2002, 277:34521-34530.
[89]Simonsson, S., and J. Gurdon. DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nat. Cell Biol 2004, 6:984-990.
[90]Tsuji-Takayama, K., T. Inoue, Y. Ijiri, T. Otani, R. Motoda, S. Nakamura, and K. Orita. Demethylating agent,5-azacytidine, reverses differentiation of embryonic stem cells. Biochem. Biophys. Res. Commun 2004,323:86-90.
[91]Sathornsumetee S,Reardon DA,Desjardins A,et al.Molecularly targeted therapy for malignant glioma.Cancer.2007;110:13-24.
[92]Shmelkov SV, Jun L, St Clair R, et al. Alternative p romoters regulate transcrip tion of the gene that encodes stem cell surface protein AC 133 [J]. Blood,2004, 103 (6):205522061.
[93]Mi Yi, Hsing-Chen Tsai, Sabine C, et al. Abnormal DNA Methylation of CD133 in Colorectal and Glioblastoma Tumors. Cancer Res 2008; 68(19): 8094-103.
[94]T Baba,PA Convery,N Matsumura, et al. Epigenetic regulation of CD133 and tumorigenicity of CD133t ovarian cancer cells. Oncogene (2009) 28,209-218.
[95]Baylin SB, Ohm JE. Epigenetic gene silencing in cancer-a mechanism for early oncogenic pathway addiction?[J].Nat Rev Cancer,2006,6(2):107-116.
[96]Esteller M, Risques RA, Toyota M, et al. Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis [J]. Cancer Res,2001,61 (12):4689-4692.
[97]Esteller M. Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes[J]. Eur J Cancer,2000,36(18):2294-2300.
[98]Tommasi S, Denissenko MF, Pfeifer GP. Sunlight induces pyrimidine dimers preferentially at 5-methylcytosine bases[J]. Cancer Res,1997,57(21):4727-4730.
[99]Chen JX, Zheng Y, West M, et al. Carcinogens preferentially bind at methylated CpG in the p53 mutational hot spots[J]. Cancer Res,1998,58(10):2070-2075.
[100]Trosko JE, Upham BL. The emperor wears no clothes in the field of carcinogen risk assessment:ignored concepts in cancer risk assessment[J]. Mutagenesis, 2005,20(2):81-92.
[101]Breathnach R, Chambon P. Organization and exp ression of eucaryotic sp lit genes coding for p roteins[J]. Annu Rev Biochem,1981,50:3492383.
[102]Shmelkov SV, St Clair R, Lyden D, et al. AC133/CD133/Prominin21 [J]. Int J Biochem Cell Biol,2005,37 (4):7152719.
[1]Louis DN, Ohgaki H, Wiestler OD,Cavenee WK, et al. WHO classifcation of tumours of the central nervous system.4th ed. Lyon, France:IARC Press,2007.
[2]Burger PC, Scheithauer BW, Paulus W,et al. Pilocytic astrocytoma. In:Kleihues P, Cavenee WK, eds. Pathology and genetics of tumours of the nervous system. Lyon, France:IARC Press,2000:45-51.
[3]Stupp R, Mason WP, van den Bent MJ,et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
[4]Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008;359:492-507.[Erratum, N Engl J Med 2008;359:877.]
[5]D.W.Parsons et al.An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science 321,1807 (2008).
[6]Devlin TM:(Ed). Textbook of biochemistry with clinical correlations. Wiley-Liss, Hoboken, N.J. (2006)
[7]Illingworth, J. A., and K. F. Tipton. Purification and properties of the nicotinamide-adenine dinucleotide phosphate-dependent isocitrate dehydrogenase from pig liver cytoplasm. Biochem. J.1970,118:253-258.
[8]Plaut, G. W., M. Cook, and T. Aogaichi. The subcellular location of isozymes of NADP-isocitrate dehydrogenase in tissues from pig, ox and rat. Biochim. Biophys. Acta 1983,760:300-308.
[9]B. S. Winkler, N. DeSantis, F. Solomon, Exp. Eye Res.43,829 (1986).
[10]Narahara K, Kimura S, Kikkawa K et al. Probable assignment of soluble isocitrate dehydrogenase (IDH1) to 2q33.3.Hum Genet 1985,71:37-40.
[11]Ramachandran, N., and R. F. Colman. Chemical characterization of distinct subunits of pig heart DPN-specific isocitrate dehydrogenase. J. Biol. Chem 1980,255:8859-8864.
[12]Keys, D. A., and L. McAlister-Henn. Subunit structure, expression, and function of NAD(H)-specific isocitrate dehydrogenase in Saccharomyces cerevisiae. J. Bacteriol 1990,172:4280-4287.
[13]Geisbrecht, B. V., and S. J. Gould. The human PICD gene encodes a cytoplasmic and peroxisomal NADP-dependent isocitrate dehydrogenase. J. Biol. Chem.1999,274:30527-30533.
[14]Yoshihara, T., T. Hamamoto, R. Munakata, R. Tajiri, M. Ohsumi, and S. Yokota. Localization of cytosolic NADP-dependent isocitrate dehydrogenase in the peroxisomes of rat liver cells:biochemical and immunocytochemical studies. J. Histochem. Cytochem 2001.49:1123-1132.
[15]Keller, G. A., M. C. Barton, D. J. Shapiro, and S. J. Singer.3-Hydroxy-3-methylglutaryl-coenzyme A reductase is present in peroxisomes in normal rat liver cells. Proc. Natl. Acad. Sci. USA 1985,82:770-774.
[16]Keller, G. A., M. Pazirandeh, and S. Krisans.3-Hydroxy-3-methylglutaryl coenzyme A reductase localization in rat liver peroxisomes and microsomes of control and cholestyramine-treated animals:quantitative biochemical and immunoelectron microscopical analyses. J. Cell Biol 1986,103:875-886.
[17]Krisans, S. K. Cell compartmentalization of cholesterol biosynthesis. Ann. N. Y. Acad. Sci 1996,804:142-164.
[18]Biardi, L., and S. K. Krisans. Compartmentalization of cholesterol biosynthesis. Conversion of mevalonate to farnesyl diphosphate occurs in the peroxisomes. J. Biol. Chem 1996,271:1784-1788.
[19]Wanders, R. J., and J. M. Tager. Lipid metabolism in peroxisomes in relation to human disease. Mol. Aspects Med 1998,19:69-154.
[20]Fransen, M., P. P. Van Veldhoven, and S. Subramani. Identification of peroxisomal proteins by using M13 phage protein VI phage display:molecular evidence that mammalian peroxisomes contain a 2,4-dienoyl-CoA reductase. Biochem. J 1999,340:561-568.
[21]Geisbrecht, B. V., X. Liang, J. C. Morrell, H. Schulz, and S. J. Gould. The mouse gene PDCR encodes a peroxisomal delta(2), delta(4)-dienoyl-CoA reductase. J. Biol. Chem.1999.274:25814-25820.
[22]Jansen, G. A., S. J. Mihalik, P. A. Watkins, H. W. Moser, C. Jakobs, S. Denis, and R. J. Wanders. Phytanoyl-CoA hydroxylase is present in human liver, located in peroxisomes, and deficient in Zellweger syndrome:direct, unequivocal evidence for the new, revised pathway of phytanic acid alpha-oxidation in humans. Biochem. Biophys. Res. Commun 1996,229: 205-210.
[23]Mihalik, S. J., A. M. Rainville, and P. A. Watkins. Phytanic acid alpha-oxidation in rat liver peroxisomes. Production of alphahydroxyphytanoyl-CoA and formate is enhanced by dioxygenase cofactors. Eur. J. Biochem 1995,232:545-551.
[24]Croes, K., M. Casteels, E. De Hoffmann, G. P. Mannaerts, and P. P. Van Veldhoven. Alpha-oxidation of 3-methyl-substituted fatty acids in rat liver. Production of formic acid instead of CO2, cofactor requirements, subcellular localization and formation of a 2-hydroxy-3-methylacyl-CoA intermediate. Eur. J. Biochem 1996,240:674-683.
[25]Verhoeven, N. M., and C. Jakobs. Human metabolism of phytanic acid and pristanic acid. Prog. Lipid Res 2001,40:453-466.
[26]Jennings, G., S. Sechi, P. Stevenson, R. Tuckey, D. Parmelee, and L. McAlister-Henn. Cytosolic NADP(_)-dependent isocitrate dehydrogenase. Isolation of rat cDNA and study of tissue-specific and developmental expression of mRNA. J. Biol. Chem 1994.269:23128-23134.
[27]Luzzatto, L., A. Mehta, and T. Vulliamy.. Glucose 6-phosphate dehydrogenase deficiency. In The Metabolic and Molecular Bases of Inherited Diseases.8th edition. Vol.3. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw-Hill, New York 2001,4517-4553.
[28]Heller, P., W. R. Best, R. B. Nelson, and J. Becktel. Clinical implications of sickle-cell trait and glucose-6-phosphate dehydrogenase deficiency in hospitalized black male patients. N. Engl. J.Med 1979,300:1001-1005.
[29]Rosenstraus, M., and L. A. Chasin. Isolation of mammalian cell mutants deficient in glucose-6-phosphate dehydrogenase activity:linkage to hypoxanthine phosphoribosyl transferase. Proc. Natl. Acad. Sci. USA 1975,72: 493-497.
[30]Town, M., M. Athanasiou-Metaxa, and L. Luzzatto. Intragenic interspecific complementation of glucose 6-phosphate dehydrogenase in human-hamster cell hybrids. Somat. Cell Mol. Genet 1990,16:97-108.
[31]Belfiore, F., and S. Iannello. Fatty acid synthesis from glutamate in the adipose tissue of normal subjects and obese patients:an enzyme study. Biochem. Mol. Med 1995,54:19-25.
[32]Lee, S. M., H. J. Koh, D. C. Park, B. J. Song, T. L. Huh, and J. W. Park. Cytosolic NADP-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic. Biol. Med 2002,32:1185-1196.
[33]Sun, L., T. T. Sun, and R. M. Lavker. Identification of a cytosolic NADP-dependent isocitrate dehydrogenase that is preferentially expressed in bovine corneal epithelium. A corneal epithelial crystallin. J. Biol. Chem. 1999.274:17334-17341.
[34]Grzeschik KH. Assignment of a gene for human mitochondrial isocitrate dehydrogenase (ICD-M, EC 1.1.1.41) to chromosome 15. Hum Genet 34:23-28.
[35]Haselbeck, R. J., and L. McAlister-Henn. Function and expression of yeast mitochondrial NAD-and NADP-specific isocitrate dehydrogenases. J. Biol. Chem.1976,268:12116-12122.
[36]Huh TL, Kim YO, Oh IU et al.Assignment of the human mitochondrial NAD-specific isocitrate dehydrogenase alpha subunit (IDH3A) gene to 15q25.1?q25.2 by in situ hybridization. Genomics 1996,32:295-296.
[37]Kim YO, Park SH, Kang YJ et al.Assignment of mitochondrial NAD-specific isocitrate dehydrogenase beta subunit gene (IDH3B) to human chromosome band 20p13 by in situ hybridization and radiation hybrid mapping. Cytogenet Cell Genet 1999,86:240-241.
[38]Weiss C, Zeng Y, Huang J et al. Bovine NAD?-dependent isocitrate dehydrogenase:alternative splicing and tissue-dependent expression of subunit 1.Biochemistry 2000,39:1807-1816.
[39]Hathaway, J. A., and Atkinson, D. E. J. Biol. Chem.1963,238,2875-2881.
[40]Balss J, Meyer J, Mueller W, et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 2008;116:597-602.
[41]Bleeker FE, Lamba S, Leenstra S, et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 2009; 30:7-11.
[42]Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360:765-773.
[43]Korshunov A, Meyer J, Capper D, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 2009; 118:401-405.
[44]Yukihiko Sonoda, Toshihiro Kumabe, Taigen Nakamura, et al. Analysis of IDH1 and IDH2 mutations in Japanes glioma patients. Cancer Sci 2009; 100: 1996-1998.
[45]Mi Ran Kang, Min Sung Kim, Ji Eun Oh, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int. J. Cancer 2009; 125:353-355.
[46]Weller M, Felsberg J, Hartmann C, et al. for the German Glioma Network. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma:A prospective translational study of the German Glioma Network. J Clin Oncol 2009; 27 (34):5743-50.
[47]Wick W, Stoffels M, Engel C, et al. for the Neurooncology Working Group (NOA) of the German Cancer Society. NOA-04 randomized phase III study of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. J Clin Oncol 2009,27(35):5874-80.
[48]Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 2009, 27(25):4150-4.
[49]Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-lalpha. Science 2009;324:261-265.
[50]Christian Hartmann, Jochen Meyer, Jorg Balss, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age:a study of 1,010 diffuse gliomas. Acta Neuropathol (2009)118:469-474.
[51]Xu X, Zhao J, Xu Z, et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem 2004; 279:33946-33957.
[52]Nekrutenko A, Hillis DM, Patton JC, et al. Cytosolic isocitrate dehydrogenase in humans, mice, and voles and phylogenetic analysis of the enzyme family. Mol Biol Evol 1998; 15:1674-1684.
[53]Koichi Ichimura, Danita M. Pearson, Sylvia Kocialkowski, et al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro-Oncology 2009,11:341-347.
[54]Cancer Genome Atlas Research Network.Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455:1061-8.
[55]Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943-7.
[56]Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989;342:705-8.
[57]Ueki K, Ono Y, Henson JW, Efird JT, von Deimling A, Louis DN. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated.Cancer Res 1996;56:150-3.
[58]Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A 1987;84:6899-903.
[59]Wong AJ, Ruppert JM, Bigner SH, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A 1992;89:2965-9.
[60]Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007; 170:1445-53.
[61]Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics,biology, and paths to treatment. Genes Dev 2007;21:2683-710.
[62]Weber RG, Sabel M, Reifenberger J, et al. Characterization of genomic alterations associated with glioma progression by comparative genomic hybridization. Oncogene 1996; 13:983-94.
[63]Bigner SH, Matthews MR, Rasheed BK, et al. Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization. Am J Pathol 1999;155:375-86.
[64]Ino Y, Betensky RA, Zlatescu MC, et al. Molecular subtypes of anaplastic oligodendroglioma:implications for patient management at diagnosis. Clin Cancer Res.2001;7:839-845.
[1]Louis DN, Ohgaki H, Wiestler OD,Cavenee WK, et al. WHO classifcation of tumours of the central nervous system.4th ed. Lyon, France:IARC Press,2007.
[2]Clark SJ, Harrison J, Frommer M. CpNpG methylation in mammalian cells. Nat Genet 1995;10:20-27.
[3]Fruhwald MC, Plass C. Global and gene-specific methylation patterns in cancer:Aspects of tumor biology and clinical potential [J]. Mol Gen. etMetab, 2002,75 (1):1-16.
[4]Bestor TH. Cloning of a mammalian DNA methyltransferase.Gene 1988;74:9-12.
[5]Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 1998; 19:219-220.
[6]Ellis L, Atadja PW, Johnstone RW1 Ep igenetics in cancer:targeting chromatin modifications [J] 1 Mol Cancer Ther,2009,6 (8):1409-1420
[7]Illingworth RS, Bird AP1 CpG islandspa rough guide [J] FEBS Lett,2009, 583 (11):1713-1720
[8]Ann E, Murray E 1 Chromatin dynamics at DNA rep lication, transcrip tion and repair [J] 1 Biochem,2004,271 (12):2335-2349
[9]OlivierM, Judith B1 RNA2directed DNA methylation [J]。J Cell Science, 2004,117 (21):4881-4888
[10]Tawa R, Ono T, Kurishita A, Okada S, Hirose S. Changes of DNA methylation level during pre-and postnatal periods in mice. Differentiation 1990;45:44-48.
[11]Ladd-Acosta C, Pevsner J, Sabunciyan S, et al. DNA methylation signatures within the human brain. Am J Hum Genet 2007;81:1304-1315.
[12]Lein ES, Hawrylycz MJ, Ao N, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 2007;445:168-176.
[13]Takizawa T, Nakashima K, Namihira M, et al. DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev Cell 2001;1:749-758.
[14]Condorelli DF, Dell'Albani P, Conticello SG, et al. A neuralspecific hypomethylated domain in the 5= flanking region of the glial fibrillary acidic protein gene. Dev Neurosci 1997; 19:446-456.
[15]Condorelli DF, Nicoletti VG, Barresi V, et al. Tissue-specific DNA methylation patterns of the rat glial fibrillary acidic protein gene. J Neurosci Res 1994;39:694-707.
[16]Goto K, Numata M, Komura JI, et al. Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation 1994;56:39-44.
[17]Inano K, Suetake I, Ueda T, et al. Maintenance-type DNA methyltransferase is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J Biochem (Tokyo) 2000;128:315-321.
[18]Trasler JM, Trasler DG, Bestor TH, Li E, Ghibu F. DNA methyltransferase in normal and Dnmtn/Dnmtn mouse embryos. Dev Dyn 1996;206:239-247.
[19]Martinowich K, Hattori D, Wu H, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003;302:890-893.
[20]Fan G, Beard C, Chen RZ, et al. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J Neurosci 2001;21:788-797.
[21]Ooi S K, Bestor T H. The colorful historyof active DNA dem2 ethylation[J]. Cell,2008,133 (7):1145-1148.
[22]Feng J, Chang H, Li E, Fan G. Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J Neurosci Res 2005;79:734-746.
[23]Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99:247-257.
[24]Nguyen S, Meletis K, Fu D, Jhaveri S, Jaenisch R. Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan. Dev Dyn 2007; 236:1663-1676.
[25]Yegnasubramanian S, Haffner MC, Zhang Y, et all DNA hypomethylation arises later in p rostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity [J] 1 Cancer Res,2008,68 (21):8954289671
[26]SyfaM, Pakneshanb P, Rabbanib SA, et all DNA methylation and breast cancer [J]1 Biochem Pharmacol,2004,68 (6):1187211971
[27]Cadieux B, Ching TT, VandenBerg SR, Costello JF. Genomewide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res 2006;66:8469-8476.
[28]Gama-Sosa MA, Slagel VA, Trewyn RW, et al. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 1983;11:6883-6894.
[29]Fanelli M, Caprodossi S, Ricci-Vitiani L, et al. Loss of pericentromeric DNA methylation pattern in human glioblastoma is associated with altered DNA methyltransferases expression and involves the stem cell compartment. Oncogene 2008;27:358-365.
[30]Yu J, Zhang H, Gu J, et al. Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma. BMC Cancer 2004;4:65.
[31]De Smet C, De Backer O, Faraoni I, et al. The activation of human gene MAGE-1 in tumor cells is correlated with genomewidegenomewide demethylation. Proc Natl Acad Sci U S A 1996;93:7149-7153.
[32]Van Der Bruggen P, Zhang Y, Chaux P, et al. Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 2002;188:51-64.
[33]Liu G, Ying H, Zeng G, et al. HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 2004;64:4980-4986.
[34]Debinski W, Obiri NI, Powers SK, Pastan I, Puri RK. Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. Clin Cancer Res 1995; 1:1253-1258.
[35]Debinski W, Gibo DM. Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumor-associated cancer/testis antigen. Mol Med 2000;6:440-449.
[36]Gaudet F, Hodgson JG, Eden A, et al. Induction of tumors in mice by genomic hypomethylation. Science 2003;300:489-492.
[37]Howard G, Eiges R, Gaudet F, Jaenisch R, Eden A. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene 2008;27:404-408.
[38]Holm TM, Jackson-Grusby L, Brambrink T, et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 2005;8:275-285.
[39]McClelland M, Ivarie R. Asymmetrical distribution of CpG in an "average" mammalian gene. Nucleic Acids Res 1982;10:7865-7877.
[40]Kimt Y, Zhong S, Fields CR, et al. Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma [J].Cancer Res,2006,66(15):7490-7501.
[41]Alaminos M, Davalos V, Ropero S, et al. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma [J]. Cancer Res, 2005,65(7):2565-2571.
[42]Maegawa S, Itaba N, Otsuka S, et al. Coordinate downregulation of a novel imprinted transcript ITUP1 with PEG3 in glioma cell lines [J]. DNA Res,2004, 11(1):37-49.
[43]Horiguchi K, Tomizawa Y, Tosaka M, et al. Epigenetic inactivation of RASSF1A candidate tumor suppressor gene at 3p21.3 in brain tumors [J]. Oncogene,2003,22(49):7862-7865.
[44]Hesson L, Bieche I, Krex D, et al. Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas [J]. Oncogene,2004,23 (13):2408-2419.
[45]Balana C, Ramirez JL, Taron M, et al. O6-methylguanine-DNA methyltransferase methylation in serum and tumor DNA predicts r esponse to 1, 3-bis (2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme [J]. Clin Cancer Res,2003,9(4):1461-1468.
[46]Cankovic M, Mikkelsen T, Rosenblum ML, et al. A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin-fixed paraffin-embedded tissue [J]. Lab Invest,2007, 87(4):392-397.
[47]Paz MF, Yaya-Tur R, Rojas-Marcos I, et al. CpG island hypermethylation of the DNA repair enzyme methyltrans-ferase predicts response to temozolomide in primary gliomas [J]. Clin Cancer Res,2004,10(15):4933-4938.
[48]Mollemann M, Wolter M, Felsberg J, et al. Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors [J]. Int J Cancer,2005,113(3):379-385.
[49]Gonzalez-Gomezo P, Bello MJ, Arjona D, et al. Promoter hypermethylation of multiple genes in astrocytic gliomas [J]. Int J Oncol,2003,22(3):601-608.
[50]Maxwell JA, Johnson SP, Quinn JA, et al. Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma [J]. Mol Cancer Ther,2006,5(10):2531-2539.
[51]Uhlmann K, Rohede K, Zeller C, et al. Distinct methylation profiles of glioma subtypes [J]. Int J Cancer,2003,106(1):52-59.
[52]Weaver K D, Grossmans A, Herman J G. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma [J]. Cancer Invest,2006,24(1):35-40.
[53]Rosenbaum E, Hoquem O, Cohen Y, et al. Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy [J]. Clin Cancer Res,2005,11(23):8321-8325.
[54]Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide [J]. Clin Cancer Res,2004,10(6):1871-1874.
[55]Alaminos M, Davalos V, Ropero S, et al. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma. Cancer Res 2005;65:2565-2571.
[56]Bruna A, Darken RS, Rojo F, et al. High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 2007;11:147-160.
[57]Waha A, Guntner S, Huang TH, et al. Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas. Neoplasia 2005;7:193-199.
[58]Zhou H, Miki R, Eeva M, et al. Reciprocal regulation of SOCS 1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme. Clin Cancer Res 2007;13:2344-2353.
[59]Zardo G, Tiirikainen MI, Hong C, et al. Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat Genet 2002;32:453-458.
[60]Gerson SL. MGMT:its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 2004;4:296-307.
[61]Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene 06-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999;59:793-797.
[62]Costello JF, Futscher BW, Kroes RA, Pieper RO. Methylationrelated chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O-6-methylguanine DNA methyltransferase gene in human glioma cell lines. Mol Cell Biol 1994; 14:6515-6521.
[63]McLendon R, Friedman A, Bigner D, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008.
[64]Lavon I, Zrihan D, Zelikovitch B, et al. Longitudinal assessment of genetic and epigenetic markers in oligodendrogliomas. Clin Cancer Res 2007;13:1429-1437.
[65]Murat A, Migliavacca E, Gorlia T, et al. Stem cell-related "selfrenewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 2008;26:3015-3024.
[66]Jelinic P, Shaw P. Loss of imprinting and cancer [J]. J Pathol,2007,211(3): 261-268.
[67]Janzen V, Forkert R, Fleming HE, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a[J]. Nature,2006,443(7110):421-426.
[68]Suzuki H, Watkins DN, Jair KW, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer[J]. Nat Genet,2004, 36(4):417-422.
[69]Holm TM, Jackson-Grusby L, Brambrink T, et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice[J]. Cancer Cell,2005,8(4): 275-285.
[70]Lee J, Son MJ, Woolard K, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 2008; 13:69-80.
[71]Shmelkov SV, Jun L, St Clair R, et al. Alternative p romoters regulate transcrip tion of the gene that encodes stem cell surface protein AC 133 [J]. Blood,2004, 103 (6):205522061.
[72]T Baba,PA Convery,N Matsumura, et al. Epigenetic regulation of CD133 and tumorigenicity of CD133t ovarian cancer cells. Oncogene (2009) 28,209-218.
[73]Mi Yi, Hsing-Chen Tsai, Sabine C, et al. Abnormal DNA Methylation of CD133 in Colorectal and Glioblastoma Tumors. Cancer Res 2008; 68(19): 8094-103.
[74]Tabu K, Sasai K, Kimura T, et al. Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Res 2008; 18:1037-1046.
[75]Wiencke JK, Zheng S, Jelluma N, et al. Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neuro Oncol 2007;9:271-279.
[76]Hong C, Maunakea A, Jun P, et al. Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8. Cancer Res 2005;65:3617-3623.
[77]Lomas J, Bello MJ, Arjona D, et al. Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas. Genes Chromosomes Cancer 2005;42:314-319.
[78]Watanabe T, Katayama Y, Yoshino A, et al. Aberrant hypermethylation of p14ARF and O6-methylguanine-DNA methyltransferase genes in astrocytoma progression. Brain Pathol 2007;17:5-10.
[79]Martinez R, Setien F, Voelter C, et al. CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme. Carcinogenesis 2007;28:1264-1268.
[80]Tews B, Roerig P, Hartmann C, et al. Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q. Oncogene 2007;26:5010-5016.
[81]Weaver KD, Grossman SA, Herman JG. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma. Cancer Invest 2006;24:35-40.
[82]Saito Y, Kanai Y, Sakamoto M, et al. Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis. Proc Natl Acad Sci U S A 2002;99:10060-10065.
[83]Ostler KR, Davis EM, Payne SL, et al. Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins. Oncogene 2007;26:5553-5563.
[84]Hong C, Moorefield KS, Jun P, et al. Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth. Proc Natl Acad Sci U S A 2007; 104:10974-10979.
[85]Moniz S, Verissimo F, Matos P, et al. Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2. Oncogene 2007;26:6071-6081.
[86]Moniz S, Matos P, Jordan P. WNK2 modulates MEK1 activity through the Rho GTPase pathway. Cell Signal 2008;20:1762-1768.
[87]Nakamura M, Konishi N, Tsunoda S, et al. Genomic alterations in human glioma cell lines detected by restriction landmark genomic scanning. J Neurooncol 1997; 34:203-209.
[88]Meissner A, Gnirke A, Bell GW, et al. Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res 2005;33:5868-5877.
[89]Weber M, Davies JJ, Wittig D, et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 2005;37:853-862.
[90]Foltz G, Ryu GY, Yoon JG, et al. Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma. Cancer Res 2006;66:6665-6674.
[91]Kongkham PN, Northcott PA, Ra YS, et al. An epigenetic genome-wide screen identifies SPINT2 as a novel tumor suppressor gene in pediatric medulloblastoma. Cancer Res 2008;68:9945-9953.
[92]Kim TY, Zhong S, Fields CR, Kim JH, Robertson KD. Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma. Cancer Res 2006;66:7490-7501.
[93]Mueller W, Nutt CL, Ehrich M, et al. Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene 2007; 26:583-593.
[94]Lee J, Kotliarova S, Kotliarov Y, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006;9:391-403.
[95]Li A, Walling J, Kotliarov Y, et al. Genomic changes and gene expression profiles reveal that established glioma cell lines are poorly representative of primary human gliomas. Mol Cancer Res 2008;6:21-30.
[2]Stupp R, Mason WP, van den Bent MJ,et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
[3]Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008; 359: 492-507.[Erratum, N Engl J Med 2008;359:877.]
[4]D.W.Parsons et al.An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science 321,1807 (2008).
[5]Balss J, Meyer J, Mueller W, et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 2008;116:597-602.
[6]Bleeker FE, Lamba S, Leenstra S, et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 2009; 30:7-11.
[7]Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360:765-773.
[8]Korshunov A, Meyer J, Capper D, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 2009; 118:401-405.
[9]Mi Ran Kang, Min Sung Kim, Ji Eun Oh, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int. J. Cancer 2009; 125:353-355.
[10]Yukihiko Sonoda, Toshihiro Kumabe, Taigen Nakamura, et al. Analysis of IDH1 and IDH2 mutations in Japanes glioma patients. Cancer Sci 2009; 100: 1996-1998.
[11]Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 2009, 27(25):4150-4.
[12]Christian Hartmann, Jochen Meyer, Jo'rg Balss, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age:a study of 1,010 diffuse gliomas. Acta Neuropathol 2009,118:469-474.
[13]Koichi Ichimura, Danita M. Pearson, Sylvia Kocialkowski, et al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro-Oncology 2009,11:341-347.
[14]Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007;170:1445-53.
[15]Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics,biology, and paths to treatment. Genes Dev 2007;21:2683-710.
[16]Weber RG, Sabel M, Reifenberger J, et al. Characterization of genomic alterations associated with glioma progression by comparative genomic hybridization. Oncogene 1996; 13:983-94.
[17]Bigner SH, Matthews MR, Rasheed BK, et al. Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization. Am J Pathol 1999;155:375-86.
[18]Jansen, G. A., S. J. Mihalik, P. A. Watkins, H. W. Moser, C. Jakobs, S. Denis, and R. J. Wanders. Phytanoyl-CoA hydroxylase is present in human liver, located in peroxisomes, and deficient in Zellweger syndrome:direct, unequivocal evidence for the new, revised pathway of phytanic acid alpha-oxidation in humans. Biochem. Biophys. Res. Commun 1996,229: 205-210.
[19]Mihalik, S. J., A. M. Rainville, and P. A. Watkins. Phytanic acid alpha-oxidation in rat liver peroxisomes. Production of alphahy-droxyphytanoyl-CoA and formate is enhanced by dioxygenase cofactors. Eur. J. Biochem 1995,232: 545-551.
[20]Croes, K., M. Casteels, E. De Hoffmann, G. P. Mannaerts, and P. P. Van Veldhoven. Alpha-oxidation of 3-methyl-substituted fatty acids in rat liver. Production of formic acid instead of CO2, cofactor requirements, subcellular localization and formation of a 2-hydroxy-3-methylacyl-CoA intermediate. Eur. J. Biochem 1996,240:674-683.
[21]Verhoeven, N. M., and C. Jakobs. Human metabolism of phytanic acid and pristanic acid. Prog. Lipid Res 2001,40:453-466.
[22]Lee, S. M., H. J. Koh, D. C. Park, B. J. Song, T. L. Huh, and J. W. Park. Cytosolic NADP-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic. Biol. Med 2002,32:1185-1196.
[23]Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 2009;324:261-265.
[24]Birner P, SchindlM, McNultyW. Hypoxia-inducible factor-1α is a marker for an unfavorable p rognosis in early stage invasive cervical cancer[J]. Cancer Res,2000,60:4693-4696.
[25]KaurB, Khwaja FW, Severson EA, et al. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis [J]. Neuro-Oncol,2005,7 (2):134-153.
[26]Zhong H, Semenza GL, Simons JW, et al. Up-regulation of hypoxia-inducible factor 1alpha is an early event in p rostate carcinogenesis[J]. CancerDetect Prev,2004,28 (2):88-93.
[27]Adelman D. M., Gertsrnstein M., Nagy A., Simon M.C., andMaltepe E. Placental cell fates are regulated in vivo by H IF-mediated hypoxia responses. Gene and Development 2000,14,3191-3203.
[28]Tomita S., Ueno M., Sakamoto M., Kitahama Y., UekiM., Maekawa N., et al. Defective brain development in mice lacking the Hif-1α gene in neural cells.Mol. Cell. Biol 2003,23:6739-6749.
[29]Singh SK, Clarkei D, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors [J]. Cancer Res,2003,63(18):5821-5828.
[30]Singh SK, Clarkei D, Hide T, et al. Cancer stem cells in nervous system tumors [J]. Oncogene,2004,23(43):7267-7273.
[31]Marx J. Mutant stem cells may seed cancer [J]. Science,2003,301(5638):1308-1310.
[32]Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma [J]. Cancer Res,2004,64(19):7011-7021.
[33]Hemmati H D, Nakano I, Lazareff J A, et al. Cancerous stem cells can arise from pediatric brain tumors [J]. Proc Nat Acad Sci USA,2003,100(25):15178-15183.
[34]Scholer HR, Ruppert S, SuzukiN, et al. New type of POU domain in germ Iine2specific p rotein Oct24 [J]. Nature,1990,344 (6265)
[35]Pesce M, Sch€oler HR. Oct-4:Gatekeeper in the beginnings of mammalian development. Stem Cells 2001,19:271-278.
[36]Monk M, Holding C. Human embryonic genes re-expressed in cancer cells. Oncogene 2001,20:8085-8091.
[37]Atlasi Y, Mowla SJ, Ziaee SA, Bahrami AR. OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer. Int J Cancer 2007,120:1598-1602.
[38]Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE. Oct4 expression in adult human stem cells:Evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis 2005,26:495-502.
[39]Webster JD, Yuzbasiyan-Gurkan V, Trosko JE, Chang CC, Kiupel M. Expression of the embryonic transcription factor Oct4 in canine neoplasms:A potential marker for stem cell subpopulations in neoplasia. Vet Pathol 2007, 44:893-900.
[40]Zhanghui Du,Deyong Jia, Shangming Liu, et al. Oct4 is Expressed in Human Gliomas and Promotes Colony Formation in Glioma Cells. GLIA 2009,57:724-733.
[41]Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma [J]. Cancer Res,2004,64(19):7011-7021.
[42]Kang MK, Kang SK. Tumorigenesis of chemotherapeutic drug2resistant cancer stem2like cells in brain glioma [J].Stem Cells Dev,2007,16 (5):837.
[43]Gonzalez J, Gilbert MR. Treatment of astrocytomas. Curr Opin Neurol. 2005; 18:632-638.
[44]Hentschel SJ, Lang FF. Current surgical management of glioblastoma. Cancer J. 2003;9:113-125.
[45]Olson JJ. Neurosurgical advances in the treatment of brain tumors. Curr Oncol Rep.2000;2:434-437.
[46]Harbaugh KS, Black PM. Strategies in the surgical management of malignant gliomas. Semin Surg Oncol.1998;14:26-33.
[47]Toms SA, Ferson DZ, Sawaya R. Basic surgical techniques in the resection of malignant gliomas. J Neuro Oncol.1999;42:215-226.
[48]Wallner KE, Galicich JH, Krol G, Arbit E,Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys.1989;16:1405-1409.
[49]Burger PC, Dubois PJ, Schold SC Jr, et al. Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg.1983;58:159-169.
[50]Gaspar LE, Fisher BJ, Macdonald DR, et al. Supratentorial malignant glioma: patterns of recurrence and implications for external beam local treatment. Int J Radiat Oncol Biol Phys.1992;24:55-57.
[51]Mitchell P, Ellison DW, Mendelow AD. Surgery for malignant gliomas: mechanistic reasoning and slippery statistics. Lancet Neurol.2005;4:413-422.
[52]Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ. Imagingbased stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg.1987;66:865-874.
[53]Brower V. Search and destroy:recent research exploits adult stem cells' attraction to cancer. J Natl Cancer Inst.2005;97:414-416.
[54]Burger PC, Heinz ER, Shibata T, Kleihues P. Topographic anatomy and CT correlations in the untreated glioblastoma multiforme. J Neurosurg. 1988;68:698-704.
[55]Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration:invasion of malignant gliomas and implications for treatment. J Clin Oncol. 2003;21:1624-1636.
[56]Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell.2007; 11:69-82.
[57]Yang ZJ. Wechsler-Reya RJ. et al. where they live:targeting the cancer stem cell niche. Cancer Cell.2007;11:3-5.
[58]Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis:epigenetics joins genetics. Trends Genet,2000,16:168-1741.
[59]Ellis L, Atadja PW, Johnstone RW1 Epigenetics in cancer:targeting chromatin modifications [J] 1 Mol Cancer Ther,2009,6 (8):1409214201.
[60]EhrichM, Turner J, Gibbs P, et al.. Cytosine methylation profiling of cancer cell lines[J]. Proc. Nat. Acad. Sci. USA,2008,105 (12):4844-4849
[61]Herman J G, Baylin S B. Gene silencing in cancer in association with p romoter hypermethylation [J]. N. Eng. J. Med.,2003,349 (21):2042-2054.
[62]Yuasa Y. DNA methylation in cancer and ageing [J]. Meeh Age ing Dev,2002, 123 (12):1649-1654.
[63]Jones PA, Laird PW. Cancer epigenetics comes of age Nat Genet 1999; 21:163-71.
[64]Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene 2001; 20:3139-31551.
[65]Yu J, Zhang H, Gu J, et al. Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma [J]. BMC Cancer,2004,4:65.
[66]Kimt Y, Zhong S, Fields CR, et al. Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma [J].Cancer Res,2006,66(15):7490-7501.
[67]Alaminson M, Davalos V, Ropero S, et al. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma [J]. Cancer Res, 2005,65(7):2565-2571.
[68]Maegawa S, Itaba N, Otsuka S, et al. Coordinate downregulation of a novel imprinted transcript ITUP1 with PEG3 in glioma cell lines [J]. DNA Res,2004, 11(1):37-49.
[69]Gao Y, Guan M, Su B, et al. Hypermethylation of the RASSF1A gene in gliomas [J]. Clin Chim Acta,2004,349 (1-2):173-179.
[70]Alonso ME, Bello MJ, Gonzalez-Gomez P, et al. Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas [J]. Cancer Genet Cytogenet,2003,144(2):134-142.
[71]Horiguchi K, Tomizawa Y, Tosaka M, et al. Epigenetic inactivation of RASSF1A candidate tumor suppressor gene at 3p21.3 in brain tumors [J]. Oncogene,2003,22(49):7862-7865.
[72]Hesson L, Bieche I, Krex D, et al. Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas [J]. Oncogene,2004,23 (13):2408-2419.
[73]Balana C, Ramirez JL, Taron M, et al. O6-methylguanine-DNA methyltransferase methylation in serum and tumor DNA predicts r esponse to 1, 3-bis (2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme [J]. Clin Cancer Res,2003,9(4):1461-1468.
[74]Cankovic M, Mikkelsen T, Rosenblum ML, et al. A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin-fixed paraffin-embedded tissue [J]. Lab Invest,2007, 87(4):392-397.
[75]Pazm F, Yaya-Tur R, Rojas-Marcos I, et al. CpG island hypermethylation of the DNA repair enzyme methyltrans-ferase predicts response to temozolomide in primary gliomas [J]. Clin Cancer Res,2004,10(15):4933-4938.
[76]Mollemann M, Wolter M, Felsberg J, et al. Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors [J]. Int J Cancer,2005,113(3):379-385.
[77]Gonzalez-Gomezo P, Bello MJ, Arjona D, et al. Promoter hypermethylation of multiple genes in astrocytic gliomas [J]. Int J Oncol,2003,22(3):601-608.
[78]Maxwell JA, Johnson SP, Quinn JA, et al. Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma [J]. Mol Cancer Ther,2006,5(10):2531-2539.
[79]Uhlmann K, Rohde K, Zeller C, et al. Distinct methylation profiles of glioma subtypes [J]. Int J Cancer,2003,106(1):52-59.
[80]Weaver KD, Grossman SA, Herman J G. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma [J]. Cancer Invest,2006,24(1):35-40.
[81]Rosenbaum E, Hoque MO, Cohen Y, et al. Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy [J]. Clin Cancer Res,2005,11(23):8321-8325.
[82]Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide [J]. Clin Cancer Res,2004,10(6):1871-1874.
[83]Robert MF, Morin S, Beaulieu N, et al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells [J]. Net Cenet, 2003,33(1):61-65.
[84]Niwa H. Molecular mechanism to maintain stem cell renewal of ES cells. Cell Struct Funct,2001,26(3):137-48
[85]Ben-Shushan, E., E. Pikarsky, A. Klar, and Y. Bergman. Extinction of Oct-3/4 gene expression in embryonal carcinoma_fibroblast somatic cell hybrids is accompanied by changes in the methylation status, chromatin structure, and transcriptional activity of the Oct-3/4 upstream region. Mol. Cell. Biol 1993, 13:891-901.
[86]Deb-Rinker, P., D. Ly, A. Jezierski, M. Sikorska, and P. R. Walker. Sequential DNA methylation of the Nanog and Oct-4 upstream regions in human NT2 cells during neuronal differentiation. J. Biol. Chem 2005,280:6257-6260.
[87]Feldman, N., A. Gerson, J. Fang, E. Li, Y. Zhang, Y. Shinkai, H. Cedar, and Y. Bergman. G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis. Nat. Cell Biol,2006(8):188-194.
[88]Gidekel, S., and Y. Bergman. A unique developmental pattern of Oct-3/4 DNA methylation is controlled by acis-demodification element. J. Biol. Chem 2002, 277:34521-34530.
[89]Simonsson, S., and J. Gurdon. DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nat. Cell Biol 2004, 6:984-990.
[90]Tsuji-Takayama, K., T. Inoue, Y. Ijiri, T. Otani, R. Motoda, S. Nakamura, and K. Orita. Demethylating agent,5-azacytidine, reverses differentiation of embryonic stem cells. Biochem. Biophys. Res. Commun 2004,323:86-90.
[91]Sathornsumetee S,Reardon DA,Desjardins A,et al.Molecularly targeted therapy for malignant glioma.Cancer.2007;110:13-24.
[92]Shmelkov SV, Jun L, St Clair R, et al. Alternative p romoters regulate transcrip tion of the gene that encodes stem cell surface protein AC 133 [J]. Blood,2004, 103 (6):205522061.
[93]Mi Yi, Hsing-Chen Tsai, Sabine C, et al. Abnormal DNA Methylation of CD133 in Colorectal and Glioblastoma Tumors. Cancer Res 2008; 68(19): 8094-103.
[94]T Baba,PA Convery,N Matsumura, et al. Epigenetic regulation of CD133 and tumorigenicity of CD133t ovarian cancer cells. Oncogene (2009) 28,209-218.
[95]Baylin SB, Ohm JE. Epigenetic gene silencing in cancer-a mechanism for early oncogenic pathway addiction?[J].Nat Rev Cancer,2006,6(2):107-116.
[96]Esteller M, Risques RA, Toyota M, et al. Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis [J]. Cancer Res,2001,61 (12):4689-4692.
[97]Esteller M. Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes[J]. Eur J Cancer,2000,36(18):2294-2300.
[98]Tommasi S, Denissenko MF, Pfeifer GP. Sunlight induces pyrimidine dimers preferentially at 5-methylcytosine bases[J]. Cancer Res,1997,57(21):4727-4730.
[99]Chen JX, Zheng Y, West M, et al. Carcinogens preferentially bind at methylated CpG in the p53 mutational hot spots[J]. Cancer Res,1998,58(10):2070-2075.
[100]Trosko JE, Upham BL. The emperor wears no clothes in the field of carcinogen risk assessment:ignored concepts in cancer risk assessment[J]. Mutagenesis, 2005,20(2):81-92.
[101]Breathnach R, Chambon P. Organization and exp ression of eucaryotic sp lit genes coding for p roteins[J]. Annu Rev Biochem,1981,50:3492383.
[102]Shmelkov SV, St Clair R, Lyden D, et al. AC133/CD133/Prominin21 [J]. Int J Biochem Cell Biol,2005,37 (4):7152719.
[1]Louis DN, Ohgaki H, Wiestler OD,Cavenee WK, et al. WHO classifcation of tumours of the central nervous system.4th ed. Lyon, France:IARC Press,2007.
[2]Burger PC, Scheithauer BW, Paulus W,et al. Pilocytic astrocytoma. In:Kleihues P, Cavenee WK, eds. Pathology and genetics of tumours of the nervous system. Lyon, France:IARC Press,2000:45-51.
[3]Stupp R, Mason WP, van den Bent MJ,et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
[4]Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med 2008;359:492-507.[Erratum, N Engl J Med 2008;359:877.]
[5]D.W.Parsons et al.An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science 321,1807 (2008).
[6]Devlin TM:(Ed). Textbook of biochemistry with clinical correlations. Wiley-Liss, Hoboken, N.J. (2006)
[7]Illingworth, J. A., and K. F. Tipton. Purification and properties of the nicotinamide-adenine dinucleotide phosphate-dependent isocitrate dehydrogenase from pig liver cytoplasm. Biochem. J.1970,118:253-258.
[8]Plaut, G. W., M. Cook, and T. Aogaichi. The subcellular location of isozymes of NADP-isocitrate dehydrogenase in tissues from pig, ox and rat. Biochim. Biophys. Acta 1983,760:300-308.
[9]B. S. Winkler, N. DeSantis, F. Solomon, Exp. Eye Res.43,829 (1986).
[10]Narahara K, Kimura S, Kikkawa K et al. Probable assignment of soluble isocitrate dehydrogenase (IDH1) to 2q33.3.Hum Genet 1985,71:37-40.
[11]Ramachandran, N., and R. F. Colman. Chemical characterization of distinct subunits of pig heart DPN-specific isocitrate dehydrogenase. J. Biol. Chem 1980,255:8859-8864.
[12]Keys, D. A., and L. McAlister-Henn. Subunit structure, expression, and function of NAD(H)-specific isocitrate dehydrogenase in Saccharomyces cerevisiae. J. Bacteriol 1990,172:4280-4287.
[13]Geisbrecht, B. V., and S. J. Gould. The human PICD gene encodes a cytoplasmic and peroxisomal NADP-dependent isocitrate dehydrogenase. J. Biol. Chem.1999,274:30527-30533.
[14]Yoshihara, T., T. Hamamoto, R. Munakata, R. Tajiri, M. Ohsumi, and S. Yokota. Localization of cytosolic NADP-dependent isocitrate dehydrogenase in the peroxisomes of rat liver cells:biochemical and immunocytochemical studies. J. Histochem. Cytochem 2001.49:1123-1132.
[15]Keller, G. A., M. C. Barton, D. J. Shapiro, and S. J. Singer.3-Hydroxy-3-methylglutaryl-coenzyme A reductase is present in peroxisomes in normal rat liver cells. Proc. Natl. Acad. Sci. USA 1985,82:770-774.
[16]Keller, G. A., M. Pazirandeh, and S. Krisans.3-Hydroxy-3-methylglutaryl coenzyme A reductase localization in rat liver peroxisomes and microsomes of control and cholestyramine-treated animals:quantitative biochemical and immunoelectron microscopical analyses. J. Cell Biol 1986,103:875-886.
[17]Krisans, S. K. Cell compartmentalization of cholesterol biosynthesis. Ann. N. Y. Acad. Sci 1996,804:142-164.
[18]Biardi, L., and S. K. Krisans. Compartmentalization of cholesterol biosynthesis. Conversion of mevalonate to farnesyl diphosphate occurs in the peroxisomes. J. Biol. Chem 1996,271:1784-1788.
[19]Wanders, R. J., and J. M. Tager. Lipid metabolism in peroxisomes in relation to human disease. Mol. Aspects Med 1998,19:69-154.
[20]Fransen, M., P. P. Van Veldhoven, and S. Subramani. Identification of peroxisomal proteins by using M13 phage protein VI phage display:molecular evidence that mammalian peroxisomes contain a 2,4-dienoyl-CoA reductase. Biochem. J 1999,340:561-568.
[21]Geisbrecht, B. V., X. Liang, J. C. Morrell, H. Schulz, and S. J. Gould. The mouse gene PDCR encodes a peroxisomal delta(2), delta(4)-dienoyl-CoA reductase. J. Biol. Chem.1999.274:25814-25820.
[22]Jansen, G. A., S. J. Mihalik, P. A. Watkins, H. W. Moser, C. Jakobs, S. Denis, and R. J. Wanders. Phytanoyl-CoA hydroxylase is present in human liver, located in peroxisomes, and deficient in Zellweger syndrome:direct, unequivocal evidence for the new, revised pathway of phytanic acid alpha-oxidation in humans. Biochem. Biophys. Res. Commun 1996,229: 205-210.
[23]Mihalik, S. J., A. M. Rainville, and P. A. Watkins. Phytanic acid alpha-oxidation in rat liver peroxisomes. Production of alphahydroxyphytanoyl-CoA and formate is enhanced by dioxygenase cofactors. Eur. J. Biochem 1995,232:545-551.
[24]Croes, K., M. Casteels, E. De Hoffmann, G. P. Mannaerts, and P. P. Van Veldhoven. Alpha-oxidation of 3-methyl-substituted fatty acids in rat liver. Production of formic acid instead of CO2, cofactor requirements, subcellular localization and formation of a 2-hydroxy-3-methylacyl-CoA intermediate. Eur. J. Biochem 1996,240:674-683.
[25]Verhoeven, N. M., and C. Jakobs. Human metabolism of phytanic acid and pristanic acid. Prog. Lipid Res 2001,40:453-466.
[26]Jennings, G., S. Sechi, P. Stevenson, R. Tuckey, D. Parmelee, and L. McAlister-Henn. Cytosolic NADP(_)-dependent isocitrate dehydrogenase. Isolation of rat cDNA and study of tissue-specific and developmental expression of mRNA. J. Biol. Chem 1994.269:23128-23134.
[27]Luzzatto, L., A. Mehta, and T. Vulliamy.. Glucose 6-phosphate dehydrogenase deficiency. In The Metabolic and Molecular Bases of Inherited Diseases.8th edition. Vol.3. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw-Hill, New York 2001,4517-4553.
[28]Heller, P., W. R. Best, R. B. Nelson, and J. Becktel. Clinical implications of sickle-cell trait and glucose-6-phosphate dehydrogenase deficiency in hospitalized black male patients. N. Engl. J.Med 1979,300:1001-1005.
[29]Rosenstraus, M., and L. A. Chasin. Isolation of mammalian cell mutants deficient in glucose-6-phosphate dehydrogenase activity:linkage to hypoxanthine phosphoribosyl transferase. Proc. Natl. Acad. Sci. USA 1975,72: 493-497.
[30]Town, M., M. Athanasiou-Metaxa, and L. Luzzatto. Intragenic interspecific complementation of glucose 6-phosphate dehydrogenase in human-hamster cell hybrids. Somat. Cell Mol. Genet 1990,16:97-108.
[31]Belfiore, F., and S. Iannello. Fatty acid synthesis from glutamate in the adipose tissue of normal subjects and obese patients:an enzyme study. Biochem. Mol. Med 1995,54:19-25.
[32]Lee, S. M., H. J. Koh, D. C. Park, B. J. Song, T. L. Huh, and J. W. Park. Cytosolic NADP-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic. Biol. Med 2002,32:1185-1196.
[33]Sun, L., T. T. Sun, and R. M. Lavker. Identification of a cytosolic NADP-dependent isocitrate dehydrogenase that is preferentially expressed in bovine corneal epithelium. A corneal epithelial crystallin. J. Biol. Chem. 1999.274:17334-17341.
[34]Grzeschik KH. Assignment of a gene for human mitochondrial isocitrate dehydrogenase (ICD-M, EC 1.1.1.41) to chromosome 15. Hum Genet 34:23-28.
[35]Haselbeck, R. J., and L. McAlister-Henn. Function and expression of yeast mitochondrial NAD-and NADP-specific isocitrate dehydrogenases. J. Biol. Chem.1976,268:12116-12122.
[36]Huh TL, Kim YO, Oh IU et al.Assignment of the human mitochondrial NAD-specific isocitrate dehydrogenase alpha subunit (IDH3A) gene to 15q25.1?q25.2 by in situ hybridization. Genomics 1996,32:295-296.
[37]Kim YO, Park SH, Kang YJ et al.Assignment of mitochondrial NAD-specific isocitrate dehydrogenase beta subunit gene (IDH3B) to human chromosome band 20p13 by in situ hybridization and radiation hybrid mapping. Cytogenet Cell Genet 1999,86:240-241.
[38]Weiss C, Zeng Y, Huang J et al. Bovine NAD?-dependent isocitrate dehydrogenase:alternative splicing and tissue-dependent expression of subunit 1.Biochemistry 2000,39:1807-1816.
[39]Hathaway, J. A., and Atkinson, D. E. J. Biol. Chem.1963,238,2875-2881.
[40]Balss J, Meyer J, Mueller W, et al. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 2008;116:597-602.
[41]Bleeker FE, Lamba S, Leenstra S, et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat 2009; 30:7-11.
[42]Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360:765-773.
[43]Korshunov A, Meyer J, Capper D, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 2009; 118:401-405.
[44]Yukihiko Sonoda, Toshihiro Kumabe, Taigen Nakamura, et al. Analysis of IDH1 and IDH2 mutations in Japanes glioma patients. Cancer Sci 2009; 100: 1996-1998.
[45]Mi Ran Kang, Min Sung Kim, Ji Eun Oh, et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int. J. Cancer 2009; 125:353-355.
[46]Weller M, Felsberg J, Hartmann C, et al. for the German Glioma Network. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma:A prospective translational study of the German Glioma Network. J Clin Oncol 2009; 27 (34):5743-50.
[47]Wick W, Stoffels M, Engel C, et al. for the Neurooncology Working Group (NOA) of the German Cancer Society. NOA-04 randomized phase III study of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. J Clin Oncol 2009,27(35):5874-80.
[48]Sanson M, Marie Y, Paris S, et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 2009, 27(25):4150-4.
[49]Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-lalpha. Science 2009;324:261-265.
[50]Christian Hartmann, Jochen Meyer, Jorg Balss, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age:a study of 1,010 diffuse gliomas. Acta Neuropathol (2009)118:469-474.
[51]Xu X, Zhao J, Xu Z, et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem 2004; 279:33946-33957.
[52]Nekrutenko A, Hillis DM, Patton JC, et al. Cytosolic isocitrate dehydrogenase in humans, mice, and voles and phylogenetic analysis of the enzyme family. Mol Biol Evol 1998; 15:1674-1684.
[53]Koichi Ichimura, Danita M. Pearson, Sylvia Kocialkowski, et al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro-Oncology 2009,11:341-347.
[54]Cancer Genome Atlas Research Network.Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455:1061-8.
[55]Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943-7.
[56]Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989;342:705-8.
[57]Ueki K, Ono Y, Henson JW, Efird JT, von Deimling A, Louis DN. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated.Cancer Res 1996;56:150-3.
[58]Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A 1987;84:6899-903.
[59]Wong AJ, Ruppert JM, Bigner SH, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A 1992;89:2965-9.
[60]Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol 2007; 170:1445-53.
[61]Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics,biology, and paths to treatment. Genes Dev 2007;21:2683-710.
[62]Weber RG, Sabel M, Reifenberger J, et al. Characterization of genomic alterations associated with glioma progression by comparative genomic hybridization. Oncogene 1996; 13:983-94.
[63]Bigner SH, Matthews MR, Rasheed BK, et al. Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization. Am J Pathol 1999;155:375-86.
[64]Ino Y, Betensky RA, Zlatescu MC, et al. Molecular subtypes of anaplastic oligodendroglioma:implications for patient management at diagnosis. Clin Cancer Res.2001;7:839-845.
[1]Louis DN, Ohgaki H, Wiestler OD,Cavenee WK, et al. WHO classifcation of tumours of the central nervous system.4th ed. Lyon, France:IARC Press,2007.
[2]Clark SJ, Harrison J, Frommer M. CpNpG methylation in mammalian cells. Nat Genet 1995;10:20-27.
[3]Fruhwald MC, Plass C. Global and gene-specific methylation patterns in cancer:Aspects of tumor biology and clinical potential [J]. Mol Gen. etMetab, 2002,75 (1):1-16.
[4]Bestor TH. Cloning of a mammalian DNA methyltransferase.Gene 1988;74:9-12.
[5]Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 1998; 19:219-220.
[6]Ellis L, Atadja PW, Johnstone RW1 Ep igenetics in cancer:targeting chromatin modifications [J] 1 Mol Cancer Ther,2009,6 (8):1409-1420
[7]Illingworth RS, Bird AP1 CpG islandspa rough guide [J] FEBS Lett,2009, 583 (11):1713-1720
[8]Ann E, Murray E 1 Chromatin dynamics at DNA rep lication, transcrip tion and repair [J] 1 Biochem,2004,271 (12):2335-2349
[9]OlivierM, Judith B1 RNA2directed DNA methylation [J]。J Cell Science, 2004,117 (21):4881-4888
[10]Tawa R, Ono T, Kurishita A, Okada S, Hirose S. Changes of DNA methylation level during pre-and postnatal periods in mice. Differentiation 1990;45:44-48.
[11]Ladd-Acosta C, Pevsner J, Sabunciyan S, et al. DNA methylation signatures within the human brain. Am J Hum Genet 2007;81:1304-1315.
[12]Lein ES, Hawrylycz MJ, Ao N, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 2007;445:168-176.
[13]Takizawa T, Nakashima K, Namihira M, et al. DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev Cell 2001;1:749-758.
[14]Condorelli DF, Dell'Albani P, Conticello SG, et al. A neuralspecific hypomethylated domain in the 5= flanking region of the glial fibrillary acidic protein gene. Dev Neurosci 1997; 19:446-456.
[15]Condorelli DF, Nicoletti VG, Barresi V, et al. Tissue-specific DNA methylation patterns of the rat glial fibrillary acidic protein gene. J Neurosci Res 1994;39:694-707.
[16]Goto K, Numata M, Komura JI, et al. Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation 1994;56:39-44.
[17]Inano K, Suetake I, Ueda T, et al. Maintenance-type DNA methyltransferase is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J Biochem (Tokyo) 2000;128:315-321.
[18]Trasler JM, Trasler DG, Bestor TH, Li E, Ghibu F. DNA methyltransferase in normal and Dnmtn/Dnmtn mouse embryos. Dev Dyn 1996;206:239-247.
[19]Martinowich K, Hattori D, Wu H, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003;302:890-893.
[20]Fan G, Beard C, Chen RZ, et al. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J Neurosci 2001;21:788-797.
[21]Ooi S K, Bestor T H. The colorful historyof active DNA dem2 ethylation[J]. Cell,2008,133 (7):1145-1148.
[22]Feng J, Chang H, Li E, Fan G. Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J Neurosci Res 2005;79:734-746.
[23]Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99:247-257.
[24]Nguyen S, Meletis K, Fu D, Jhaveri S, Jaenisch R. Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan. Dev Dyn 2007; 236:1663-1676.
[25]Yegnasubramanian S, Haffner MC, Zhang Y, et all DNA hypomethylation arises later in p rostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity [J] 1 Cancer Res,2008,68 (21):8954289671
[26]SyfaM, Pakneshanb P, Rabbanib SA, et all DNA methylation and breast cancer [J]1 Biochem Pharmacol,2004,68 (6):1187211971
[27]Cadieux B, Ching TT, VandenBerg SR, Costello JF. Genomewide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation. Cancer Res 2006;66:8469-8476.
[28]Gama-Sosa MA, Slagel VA, Trewyn RW, et al. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 1983;11:6883-6894.
[29]Fanelli M, Caprodossi S, Ricci-Vitiani L, et al. Loss of pericentromeric DNA methylation pattern in human glioblastoma is associated with altered DNA methyltransferases expression and involves the stem cell compartment. Oncogene 2008;27:358-365.
[30]Yu J, Zhang H, Gu J, et al. Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma. BMC Cancer 2004;4:65.
[31]De Smet C, De Backer O, Faraoni I, et al. The activation of human gene MAGE-1 in tumor cells is correlated with genomewidegenomewide demethylation. Proc Natl Acad Sci U S A 1996;93:7149-7153.
[32]Van Der Bruggen P, Zhang Y, Chaux P, et al. Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 2002;188:51-64.
[33]Liu G, Ying H, Zeng G, et al. HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 2004;64:4980-4986.
[34]Debinski W, Obiri NI, Powers SK, Pastan I, Puri RK. Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. Clin Cancer Res 1995; 1:1253-1258.
[35]Debinski W, Gibo DM. Molecular expression analysis of restrictive receptor for interleukin 13, a brain tumor-associated cancer/testis antigen. Mol Med 2000;6:440-449.
[36]Gaudet F, Hodgson JG, Eden A, et al. Induction of tumors in mice by genomic hypomethylation. Science 2003;300:489-492.
[37]Howard G, Eiges R, Gaudet F, Jaenisch R, Eden A. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene 2008;27:404-408.
[38]Holm TM, Jackson-Grusby L, Brambrink T, et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 2005;8:275-285.
[39]McClelland M, Ivarie R. Asymmetrical distribution of CpG in an "average" mammalian gene. Nucleic Acids Res 1982;10:7865-7877.
[40]Kimt Y, Zhong S, Fields CR, et al. Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma [J].Cancer Res,2006,66(15):7490-7501.
[41]Alaminos M, Davalos V, Ropero S, et al. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma [J]. Cancer Res, 2005,65(7):2565-2571.
[42]Maegawa S, Itaba N, Otsuka S, et al. Coordinate downregulation of a novel imprinted transcript ITUP1 with PEG3 in glioma cell lines [J]. DNA Res,2004, 11(1):37-49.
[43]Horiguchi K, Tomizawa Y, Tosaka M, et al. Epigenetic inactivation of RASSF1A candidate tumor suppressor gene at 3p21.3 in brain tumors [J]. Oncogene,2003,22(49):7862-7865.
[44]Hesson L, Bieche I, Krex D, et al. Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas [J]. Oncogene,2004,23 (13):2408-2419.
[45]Balana C, Ramirez JL, Taron M, et al. O6-methylguanine-DNA methyltransferase methylation in serum and tumor DNA predicts r esponse to 1, 3-bis (2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme [J]. Clin Cancer Res,2003,9(4):1461-1468.
[46]Cankovic M, Mikkelsen T, Rosenblum ML, et al. A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin-fixed paraffin-embedded tissue [J]. Lab Invest,2007, 87(4):392-397.
[47]Paz MF, Yaya-Tur R, Rojas-Marcos I, et al. CpG island hypermethylation of the DNA repair enzyme methyltrans-ferase predicts response to temozolomide in primary gliomas [J]. Clin Cancer Res,2004,10(15):4933-4938.
[48]Mollemann M, Wolter M, Felsberg J, et al. Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors [J]. Int J Cancer,2005,113(3):379-385.
[49]Gonzalez-Gomezo P, Bello MJ, Arjona D, et al. Promoter hypermethylation of multiple genes in astrocytic gliomas [J]. Int J Oncol,2003,22(3):601-608.
[50]Maxwell JA, Johnson SP, Quinn JA, et al. Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma [J]. Mol Cancer Ther,2006,5(10):2531-2539.
[51]Uhlmann K, Rohede K, Zeller C, et al. Distinct methylation profiles of glioma subtypes [J]. Int J Cancer,2003,106(1):52-59.
[52]Weaver K D, Grossmans A, Herman J G. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma [J]. Cancer Invest,2006,24(1):35-40.
[53]Rosenbaum E, Hoquem O, Cohen Y, et al. Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy [J]. Clin Cancer Res,2005,11(23):8321-8325.
[54]Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide [J]. Clin Cancer Res,2004,10(6):1871-1874.
[55]Alaminos M, Davalos V, Ropero S, et al. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma. Cancer Res 2005;65:2565-2571.
[56]Bruna A, Darken RS, Rojo F, et al. High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene. Cancer Cell 2007;11:147-160.
[57]Waha A, Guntner S, Huang TH, et al. Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas. Neoplasia 2005;7:193-199.
[58]Zhou H, Miki R, Eeva M, et al. Reciprocal regulation of SOCS 1 and SOCS3 enhances resistance to ionizing radiation in glioblastoma multiforme. Clin Cancer Res 2007;13:2344-2353.
[59]Zardo G, Tiirikainen MI, Hong C, et al. Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors. Nat Genet 2002;32:453-458.
[60]Gerson SL. MGMT:its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer 2004;4:296-307.
[61]Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene 06-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999;59:793-797.
[62]Costello JF, Futscher BW, Kroes RA, Pieper RO. Methylationrelated chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O-6-methylguanine DNA methyltransferase gene in human glioma cell lines. Mol Cell Biol 1994; 14:6515-6521.
[63]McLendon R, Friedman A, Bigner D, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008.
[64]Lavon I, Zrihan D, Zelikovitch B, et al. Longitudinal assessment of genetic and epigenetic markers in oligodendrogliomas. Clin Cancer Res 2007;13:1429-1437.
[65]Murat A, Migliavacca E, Gorlia T, et al. Stem cell-related "selfrenewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 2008;26:3015-3024.
[66]Jelinic P, Shaw P. Loss of imprinting and cancer [J]. J Pathol,2007,211(3): 261-268.
[67]Janzen V, Forkert R, Fleming HE, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a[J]. Nature,2006,443(7110):421-426.
[68]Suzuki H, Watkins DN, Jair KW, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer[J]. Nat Genet,2004, 36(4):417-422.
[69]Holm TM, Jackson-Grusby L, Brambrink T, et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice[J]. Cancer Cell,2005,8(4): 275-285.
[70]Lee J, Son MJ, Woolard K, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 2008; 13:69-80.
[71]Shmelkov SV, Jun L, St Clair R, et al. Alternative p romoters regulate transcrip tion of the gene that encodes stem cell surface protein AC 133 [J]. Blood,2004, 103 (6):205522061.
[72]T Baba,PA Convery,N Matsumura, et al. Epigenetic regulation of CD133 and tumorigenicity of CD133t ovarian cancer cells. Oncogene (2009) 28,209-218.
[73]Mi Yi, Hsing-Chen Tsai, Sabine C, et al. Abnormal DNA Methylation of CD133 in Colorectal and Glioblastoma Tumors. Cancer Res 2008; 68(19): 8094-103.
[74]Tabu K, Sasai K, Kimura T, et al. Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Res 2008; 18:1037-1046.
[75]Wiencke JK, Zheng S, Jelluma N, et al. Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma. Neuro Oncol 2007;9:271-279.
[76]Hong C, Maunakea A, Jun P, et al. Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8. Cancer Res 2005;65:3617-3623.
[77]Lomas J, Bello MJ, Arjona D, et al. Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas. Genes Chromosomes Cancer 2005;42:314-319.
[78]Watanabe T, Katayama Y, Yoshino A, et al. Aberrant hypermethylation of p14ARF and O6-methylguanine-DNA methyltransferase genes in astrocytoma progression. Brain Pathol 2007;17:5-10.
[79]Martinez R, Setien F, Voelter C, et al. CpG island promoter hypermethylation of the pro-apoptotic gene caspase-8 is a common hallmark of relapsed glioblastoma multiforme. Carcinogenesis 2007;28:1264-1268.
[80]Tews B, Roerig P, Hartmann C, et al. Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q. Oncogene 2007;26:5010-5016.
[81]Weaver KD, Grossman SA, Herman JG. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma. Cancer Invest 2006;24:35-40.
[82]Saito Y, Kanai Y, Sakamoto M, et al. Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3b4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis. Proc Natl Acad Sci U S A 2002;99:10060-10065.
[83]Ostler KR, Davis EM, Payne SL, et al. Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins. Oncogene 2007;26:5553-5563.
[84]Hong C, Moorefield KS, Jun P, et al. Epigenome scans and cancer genome sequencing converge on WNK2, a kinase-independent suppressor of cell growth. Proc Natl Acad Sci U S A 2007; 104:10974-10979.
[85]Moniz S, Verissimo F, Matos P, et al. Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2. Oncogene 2007;26:6071-6081.
[86]Moniz S, Matos P, Jordan P. WNK2 modulates MEK1 activity through the Rho GTPase pathway. Cell Signal 2008;20:1762-1768.
[87]Nakamura M, Konishi N, Tsunoda S, et al. Genomic alterations in human glioma cell lines detected by restriction landmark genomic scanning. J Neurooncol 1997; 34:203-209.
[88]Meissner A, Gnirke A, Bell GW, et al. Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis. Nucleic Acids Res 2005;33:5868-5877.
[89]Weber M, Davies JJ, Wittig D, et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 2005;37:853-862.
[90]Foltz G, Ryu GY, Yoon JG, et al. Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma. Cancer Res 2006;66:6665-6674.
[91]Kongkham PN, Northcott PA, Ra YS, et al. An epigenetic genome-wide screen identifies SPINT2 as a novel tumor suppressor gene in pediatric medulloblastoma. Cancer Res 2008;68:9945-9953.
[92]Kim TY, Zhong S, Fields CR, Kim JH, Robertson KD. Epigenomic profiling reveals novel and frequent targets of aberrant DNA methylation-mediated silencing in malignant glioma. Cancer Res 2006;66:7490-7501.
[93]Mueller W, Nutt CL, Ehrich M, et al. Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene 2007; 26:583-593.
[94]Lee J, Kotliarova S, Kotliarov Y, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006;9:391-403.
[95]Li A, Walling J, Kotliarov Y, et al. Genomic changes and gene expression profiles reveal that established glioma cell lines are poorly representative of primary human gliomas. Mol Cancer Res 2008;6:21-30.