Epigenetic Analyses of Brain Tumors for Development of Diagnosis and Treatment in the Era of Postgenome

• Project/Area Number: 19591669
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Nagoya University
• Principal Investigator: NATSUME Atsushi Nagoya University, 医学部附属病院, 特任准教授 (30362255)
• Co-Investigator(Kenkyū-buntansha): YOSHIDA Jun 名古屋大学, 大学院・医学系研究科, 教授 (40158449)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 脳腫瘍 / 遺伝子 / ゲノム / エピジェネティクス / 診断 / 治療 / DNAメチル化 / MGMT / パイロシークエンス / マイクロアレイ / 脳腫瘍幹細胞 / 免疫療法 / 組織培養 / 脳腫瘍の起源

Research Abstract

本研究では、pyrosequenceを用いてエピジェネティクなDNAメチル化変化を定量することを試みた。Pyrosequence法は、従来のmethylation-specific PCR(MSP)の不定量性を改良した斬新な方法である。MSPでは、メチル化の有無しか判定できないのに対し、Pyrosequencingではグリオーマの腫瘍組織は0-90%にわたる広範囲なメチル化が起こることを認めた。基準値を設けるとMSPとの相関も認められた。また、免疫組織染色との相関、テモゾロミドを投与した神経膠腫症例における予後との相関についても検討した。

Research Products

• [Journal Article] Interferon-beta, MCNU, and conventional radiotherapy for pediatric patients with brainstem glioma (2009)
  • Author(s): Ohno M, Natsume A, Fujii M
  • Journal Title: Pediatr Blood Cancer (in press)
• [Journal Article] p16 promoter methylation in the serum as a basis for the molecular diagnosis of gliomas (2009)
  • Author(s): Wakabayashi T, Natsume A, Hatano H
  • Journal Title: Neurosurgery 64(3)
• [Journal Article] Synergistic induction of NY-ESO-1 antigen expression by a novel histone deacetylase inhibitor, valproic acid, with 5-aza-2'-deoxycytidine in glioma cells (2009)
  • Author(s): Oi S, Natsume A, Ito M
  • Journal Title: J Neurooncol 92(1) Pages: 15-22
• [Journal Article] Type I Interferon Inhibits Astrocytic Gliosis and Promotes Functional Recovery after Spinal Cord Injury by Deactivation of the MEK/ERK Pathway (2009)
  • Author(s): Ito M, Natsume A, Takeuchi H
  • Journal Title: J Neurotrauma 26(1) Pages: 41-53
• [Journal Article] Type I Interferon Inhibits Astrocytic Gliosis and Promotes Functional Recovery after Spinal Cord Injury by Deactivation of the MEK/ERK Path way. (2009)
  • Author(s): Ito M, Natsume A, Takeuchi H, et al.
  • Journal Title: J Neurotrauma 26 Pages: 41-53
  • Peer Reviewed
• [Journal Article] Interferon-beta, MCNU, and conventional radiotherapy for pediatric patients with brainstem glioma. (2009)
  • Author(s): Ohno M, Natsume A, Fujii M, et al.
  • Journal Title: Pediatr Blood Cancer (In press)
  • Peer Reviewed
• [Journal Article] Synergistic induction of NY-ESO-1 antigen expression by a novel histone deacetylase inhibitor, valproic acid, with 5-aza-2'-deoxycytidine in glioma cells. (2009)
  • Author(s): Oi S, Natsume A, Ito M, et al.
  • Journal Title: J Neurooncol 92 Pages: 15-22
  • Peer Reviewed
• [Journal Article] p16 promoter methylation in the serum as a basis for the molecular diagnosis of gliomas. (2009)
  • Author(s): Wakabayashi T, Natsume A., Hatano H, et al.
  • Journal Title: Neurosurgery 64 Pages: 461-452
  • Peer Reviewed
• [Journal Article] A phase I clinical trial of interferon-beta gene therapy for high- grade glioma : novel findings from gene expression profiling and autopsy (2008)
  • Author(s): Wakabayashi T, Natsume A, Hashizume Y
  • Journal Title: J Gene Med 10(4) Pages: 329-339
• [Journal Article] A multicenter phase I trial of interferon-beta and temozolomide combination therapy for high-grade gliomas (INTEGRA Study) (2008)
  • Author(s): Wakabayashi T, Kayama T, Nishikawa R
  • Journal Title: Jpn J Clin Oncol 38(10) Pages: 715-718
• [Journal Article] Identification of a human leukocyte antigen-A24-restricted T-cell epitope derived from interleukin-13 receptor alpha2 chain, a glioma-associated antigen (2008)
  • Author(s): Shimato S, Natsume A, Wakabayashi T
  • Journal Title: J Neurosurg 109(1) Pages: 117-122
• [Journal Article] Gene therapy for high-grade glioma : current approaches and future directions (2008)
  • Author(s): Natsume A, Yoshida J
  • Journal Title: Cell Adh Migr 2(3) Pages: 186-191
• [Journal Article] The DNA demethylating agent 5-aza-2'-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma (2008)
  • Author(s): Natsume A, Wakabayashi T, Tsujimura K
  • Journal Title: Int J Cancer 122(11) Pages: 2542-2553
• [Journal Article] A combination of IFN-beta and temozolomide in human glioma xenograft models : implication of p53-mediated MGMT downregulation (2008)
  • Author(s): Natsume A, Wakabayashi T, Ishii D
  • Journal Title: Cancer Chemother Pharmacol 61(4) Pages: 653-659
• [Journal Article] Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas (2008)
  • Author(s): Gao W, Kondo Y, Shen L
  • Journal Title: Carcinogenesis 29(10) Pages: 1901-1910
• [Journal Article] A combination of IFN-beta and temozolomide in human glioma xenograft models : implication of p53-inediated MGMT downregulation. (2008)
  • Author(s): Natsume A, Wakabayashi T, Ishii D, et al.
  • Journal Title: Cancer Chemother Pharmacol 61 Pages: 653-659
  • Peer Reviewed
• [Journal Article] The DNA demethylating agent 5-aza-2'-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma. (2008)
  • Author(s): Natsume A, Wakabayashi T, Tsujimura K, et al.
  • Journal Title: Int J Cancer 122 Pages: 2542-2553
  • Peer Reviewed
• [Journal Article] Gene therapy for high-grade glioma : current approaches and future directions. (2008)
  • Author(s): Natsume A, Yoshida J
  • Journal Title: Cell Adh Migr 2 Pages: 186-191
  • Peer Reviewed
• [Journal Article] Identification of a human leukocyte antigen-A24-restricted T-cell epitope derived from interleukin-13 receptor alpha2 chain, a glioma-associated antigen. (2008)
  • Author(s): Shimato S, Natsume A, Wakabayashi T, et al.
  • Journal Title: J Neurosurg 109 Pages: 117-122
  • Peer Reviewed
• [Journal Article] A phase I clinical trial of interferon-beta gene therapy for high-grade glioma : novel findings from gene expression profiling and autopsy. (2008)
  • Author(s): Wakabayashi T, Natsume A, Hashizume Y, et al.
  • Journal Title: J Gene Med 10 Pages: 329-339
  • Peer Reviewed
• [Journal Article] Inhibition of Aurora-B function increases formation of multinucleated cells in p53 gene deficient cells and enhances anti-tumor effect of temozolomide in human glioma cells (2007)
  • Author(s): Tsuno T, Natsume A, Katsumata S
  • Journal Title: J Neurooncol 83(3) Pages: 249-258
• [Journal Article] Intravenously transplanted human neural stem cells migrate to the injured spinal cord in adult mice in an SDF-1- and HGF-dependent manner (2007)
  • Author(s): Takeuchi H, Natsume A, Wakabayashi T
  • Journal Title: Neurosci Lett 426(2) Pages: 69-74
• [Journal Article] Human neural stem cells target and deliver therapeutic gene to experimental leptomeningeal medulloblastoma (2007)
  • Author(s): Shimato S, Natsume A, Takeuchi H
  • Journal Title: Gene Ther 14(15) Pages: 1132-1142
• [Journal Article] Malignant transformation-related genes in meningiomas : allelic loss on 1p36 and methylation status of p73 and RASSF1A (2007)
  • Author(s): Nakane Y, Natsume A, Wakabayashi T
  • Journal Title: J Neurosurg 107(2) Pages: 398-404
• [Journal Article] Genetically heterogeneous glioblastoma recurring with disappearance of 1p/19q losses : case report (2007)
  • Author(s): Ito M, Wakabayashi T, Natsume A
  • Journal Title: Neurosurgery 61(1)
• [Journal Article] The free-radical scavenger edaravone restores the differentiation of human neural precursor cells after radiation-induced oxidative stress (2007)
  • Author(s): Ishii J, Natsume A, Wakabayashi T
  • Journal Title: Neurosci Lett 423(3) Pages: 225-230
• [Journal Article] Efficacy of temozolomide is correlated with 1p loss and methylation of the deoxyribonucleic acid repair gene MGMT in malignant gliomas (2007)
  • Author(s): Ishii D, Natsume A, Wakabayashi T
  • Journal Title: Neurol Med Chir (Tokyo) 47(8) Pages: 341-349
  • NAID: 110006368605
• [Journal Article] Efficacy of temozolomide is correlated with 1p Loss and Methylation of the Deoxyribonucleic Acid Repair Gene MGMT in Malignant Gliomas (2007)
  • Author(s): Ishii D, Natsume A, Wakabayashi T, Hatano H, Asano Y, Takeuchi H, Shimato S, Ito M, Fujii M, Yoshida J.
  • Journal Title: Neurol Med Chir (Tokyo) 47 Pages: 341-350
  • NAID: 110006368605
  • Peer Reviewed
• [Journal Article] Genetically heterogenous glioblastoma recurring with disappearance of 1p/19q losses: case report (2007)
  • Author(s): Ito M, Wakabayashi T, Natsume A, Hatano H, Fujii M, Yoshida J.
  • Journal Title: Neurosurgery 61 Pages: 168-169
  • Peer Reviewed
• [Journal Article] Malignant transformation-related genes in meningioma: allelic loss on 1 p36 and methylation status of p73 and RASSF1A (2007)
  • Author(s): Nakane Y, Natsume A, Wakabayashi T, Oi S, Ito M, Inao S, Saito K, Yoshida J.
  • Journal Title: J Neurosurg 107 Pages: 398-404
  • Peer Reviewed
• [Presentation] 脳腫瘍幹細胞の起源 : エピジェネティクス解析とポリコーム蛋白標的治療の開発 (2008)
  • Author(s): 夏目敦至
  • Organizer: 第26回日本脳腫瘍学会
  • Place of Presentation: 愛媛県
• [Presentation] 脳腫瘍治療の最近の進歩 (2008)
  • Author(s): 夏目敦至
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] グリオーマ幹細胞に対する分子標的治療の開発 (2008)
  • Author(s): 夏目敦至
  • Organizer: 第67回日本脳神経外科学会総会
  • Place of Presentation: 盛岡
• [Presentation] Characteristics of AtypicalMeningiomas (2008)
  • Author(s): Natsume,A
  • Organizer: 6th International Congress on Meningiomas and Cerebral Venous System
  • Place of Presentation: Boston, MA, USA
• [Presentation] グリオーマ幹細胞の網羅的エピジェネティクス解析 (2008)
  • Author(s): 夏目敦至
  • Organizer: 第9回日本分子脳神経外科学会
  • Place of Presentation: 京都
• [Presentation] TARGETING OF GLIOMA CELLS EXPRESSING THE EGFR TYPE 3 VARIANT USING GENETICALLY ENGINEERED T-CELLS (2008)
  • Author(s): Natsume, A
  • Organizer: The 14th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Sapporo
• [Presentation] NEURAL STEM CELLS TRANSDUCED WITH THE IFN-beta AND CYTOSINE DEAMINASE GENES ENHANCE BYSTANDER EFFECT IN EXPERIMENTAL GLIOMAS (2008)
  • Author(s): Natsume, A
  • Organizer: The 14th Annual Meeting of Japan Society of Gene Therapy
  • Place of Presentation: Sapporo
• [Presentation] THE DNA DEMETHYLATING AGENT 5- AZA-2-DEOXYCYTIDINE INDUCES THE EXPRESSION OF CANCER-TESTIS ANTIGENS IN HUMAN GLIOMAS : EPIGENETIC TARGET FOR TUMOR IMMUNOTHERAPY (2008)
  • Author(s): Natsume, A
  • Organizer: The 17th International Conference on Brain Tumor Research and Therapy
  • Place of Presentation: Hakodate, Japan
• [Presentation] A JAPANESE MULTICENTER CLINICAL TRIAL OF INTERFERON-B AND TEMOZOLOMIDE COMBINATION THERAPY FOR HIGH-GRADE GLIOMAS : FROM BENCH TO BEDSIDE (2008)
  • Author(s): Natsume, A
  • Organizer: The 17th International Conference on Brain Tumor Research and Therapy
  • Place of Presentation: Hakodate, Japan
• [Presentation] GLOBAL ANALYSES OF POLYCOMB MEDIATED TRANSCRPTIONALREPRESSION AND DNA METHYLATION TARGETS IN BRAIN TUMOR STEM CELLS (2008)
  • Author(s): Natsume, A
  • Organizer: The 17th International Conference on Brain Tumor Research and Therapy
  • Place of Presentation: Hakodate, Japan
• [Presentation] ポストゲノム時代のエピジェネティクス解析 : MGMT遺伝子メチル化の定量の試み (2008)
  • Author(s): 夏目敦至
  • Organizer: 第26回 日本脳腫瘍病理学会
  • Place of Presentation: 東京
• [Presentation] A JAPANESE MULTICENTER CLINICAL TRIAL OF INTERFERON-B AND TEMOZOLOMIDE COMBINATION THERAPY FOR HIGH-GRADE GLIOMAS : FROM BENCH TO BEDSIDE. (2008)
  • Author(s): Natsume A
  • Organizer: The 17th International Conference on Brain Tum or Research and Therapy.
  • Place of Presentation: Hakodate, Japan
• [Presentation] GLOBAL ANALYSES OF POLYCOMB MEDIATED TRANSCRPTIONALREPRESSION AND DNA METHYLATION TARGETS IN BRAIN TUMOR STEM CELLS. (2008)
  • Author(s): Natsume A
  • Organizer: The 17th International Conference on Brain Tum or Research and Therapy.
  • Place of Presentation: Hakodate, Japan
• [Presentation] THE DNA DEMETHYLATING AGENT 5- AZA-2-DEOXYCYTIDINE INDUCES THE EXPRESSION OF CANCER-TESTIS ANTIGENS IN HUMAN GLIOMAS : EPIGENETIC TAEGET FOR TUMOR IMMUNOTHERAPY. (2008)
  • Author(s): Natsume A
  • Organizer: The 17th International Conference on Brain Tum or Research and Therapy.
  • Place of Presentation: Hakodate, Japan
• [Presentation] Characteristics of AtjnpicalMenmgiomas. (2008)
  • Author(s): Natsume A
  • Organizer: 6th International Congress on Meningiomas and Cerebral Venous System.
  • Place of Presentation: Boston, MA< USA
• [Presentation] グリオーマ幹細胞の網羅的エピジェネティクス解析 (2007)
  • Author(s): 夏目敦至
  • Organizer: 第25回日本脳腫瘍学会
  • Place of Presentation: 東京
• [Presentation] バルプロ酸とDNAメチル化酵素阻害薬による (2007)
  • Author(s): 夏目敦至
  • Organizer: グリオーマの癌精巣抗原遺伝子のクロマチン構造変化第25回日本脳腫瘍学会
  • Place of Presentation: 東京
• [Presentation] Epigenetic target for cancer-testis antigen-based tumor immunotherapy (2007)
  • Author(s): 夏目敦至
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] グリオーマ幹細胞の網羅的エピジェネティクス解析 (2007)
  • Author(s): 夏目敦至
  • Organizer: 第66回日本脳神経外科学会総会
  • Place of Presentation: 東京
• [Book] グリオーマのエピジェネティクス解析(黒岩敏彦) (2009)
  • Author(s): 夏目敦至
  • Total Pages: 164
  • Publisher: 金芳堂
• [Book] 脳21 (2009)
  • Author(s): 夏目敦至
  • Total Pages: 146
  • Publisher: 金芳堂
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/cgrm/
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/cgrm/