Mechanistic insight into malignant transformation and therapeutic strategies based on the comparative multi-omics analysis of primary and recurrent gliomas

• Project/Area Number: 26293321
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kumamoto University (2017); The University of Tokyo (2014-2016)
• Principal Investigator: Mukasa Akitake 熊本大学, 大学院生命科学研究部(医), 教授 (90463869)
• Co-Investigator(Kenkyū-buntansha): 田中 將太 東京大学, 医学部附属病院, 助教 (80643725)
• Co-Investigator(Renkei-kenkyūsha): SAITO Kuniaki 杏林大学, 医学部, 助教 (50446564)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: 悪性神経膠腫 / ゲノム / エピゲノム / 腫瘍内多様性 / 治療抵抗性

Outline of Final Research Achievements

To understand the changes of the molecular profile during tumor progression and to develop a proper treatment strategy, multi “omics” analysis was performed in approximately 122 gliomas that includes 22 paired samples of primary and recurrent tumors with exome sequencing and RNA-sequencing, as well as Infinium 450K methylation chip. The integrated bioinformatics analysis revealed that a large proportion of recurrent tumors had markedly different set of mutations and showed branched evolution pattern. Some malignantly transformed diffuse astrocytomas previously treated by temozolomide acquired numerous de novo mutations accompanying mutations in mismatch repair genes and showed a “hypermutator phenotype”. Genome-wide DNA methylation analysis revealed characteristic DNA demethylation during malignant progression in a subset diffuse astrocytomas. Interestingly, we found that most loci that were demethylated during malignant progression were located outside of CpG islands.

Research Products

• [Journal Article] Saito N. Genetic and epigenetic stability of oligodendrogliomas at recurrence. (2017)
  • Author(s): Aihara K, Mukasa A, Nagae G, Nomura M, Yamamoto S, Ueda H, Tatsuno K, Shibahara J, Takahashi M, Momose T, Tanaka S, Takayanagi S, Yanagisawa S, Nejo T, Takahashi S, Omata M, Otani R, Saito K, Narita Y, Nagane M, Nishikawa R, Ueki K, Aburatani H, Saito N
  • Journal Title: Acta Neuropathologica Communications Volume: 5 Pages: 1-11
  • DOI: 10.1186/s40478-017-0422-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An automated voxel-based method for calculating the reference value for a brain tumour metabolic index using 18F-FDG-PET and 11C-methionine PET (2017)
  • Author(s): Takahashi, Soma T, Mukasa A, Koyama, Arai T, Momose T.
  • Journal Title: Annals of Nuclear Medicine Volume: 31 Pages: 250-259
  • DOI: 10.1007/s12149-017-1153-8
  • Peer Reviewed / Open Access
• [Journal Article] A prospective multicenter single-arm clinical trial of bevacizumab for patients with surgically untreatable symptomatic brain radiation necrosis (2016)
  • Author(s): Furuse M, Nonoguchi N, Kuroiwa T, Miyamoto S, Arakawa Y, Shinoda J, Miwa K, Iuchi T, K, Houkin K, Terasaka S, Tabei Y, Nakamura H, Nagane M, Sugiyama K, Terasaki M, Abe T, Narita Y, Saito N, Mukasa A, Ogasawara K, Beppu T, Kumabe T, Nariai T, Tsuyuguchi N, Nakatani E, Kurisu S, Naakagawa Y, Miyatake S.
  • Journal Title: Neurooncol Pract. Volume: 0 Pages: 272-280
  • DOI: 10.1093/nop/npv064
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas (2016)
  • Author(s): Arita H, Yamasaki K, Matsushita Y, Nakamura T, Shimokawa A, Takami H, Tanaka S, Mukasa A, Shirahata M, Shimizu S, Suzuki K, Saito K, Kobayashi K, Higuchi F, Uzuka T, Otani R, Tamura K, Sumita K, Ohno M, Miyakita Y, Kagawa N, Hashimoto N, Hatae R, Yoshimoto K, Shinojima N, Nakamura H, Kanemura Y, Okita Y, et al.
  • Journal Title: Acta Neuropathol Commun Volume: 4 Pages: 1-14
  • DOI: 10.1186/s40478-016-0351-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma. (2016)
  • Author(s): Nagashima H, Tanaka K, Sasayama T, Irino Y, Sato N, Takeuchi Y, Kyotani K, Mukasa A, Mizukawa K, Sakata J, Yamamoto Y, Hosoda K, Itoh T, Sasaki R, Kohmura E.
  • Journal Title: Neuro Oncol. Volume: 18(11) Pages: 1559-1568
  • DOI: 10.1093/neuonc/now090
  • Peer Reviewed
• [Journal Article] Utility of ATRX immunohistochemistry in diagnosis of adult diffuse gliomas. (2016)
  • Author(s): Ikemura M, Shibahara J, Mukasa A, Takayanagi S, Aihara K, Saito N, Aburatani H, Fukayama M.
  • Journal Title: Histopathology. Volume: 印刷中
  • DOI: 10.1111/his.12927
  • Peer Reviewed
• [Journal Article] Genomic characterization of primary central nervous system lymphoma. (2016)
  • Author(s): Fukumura K, Kawazu M, Kojima S, Ueno T, Sai E, Soda M, Ueda H, Yasuda T, Yamaguchi H, Lee J, Shishido-Hara Y, Sasaki A, Shirahata M, Mishima K, Ichimura K, Mukasa A, Narita Y, Saito N, Aburatani H, Nishikawa R, Nagane M, Mano H
  • Journal Title: Acta Neuropathol Volume: Epub
  • Peer Reviewed
• [Journal Article] Findings from positron emission tomography and genetic analyses for cerebellar liponeurocytoma. (2015)
  • Author(s): Takami H, Mukasa A, Ikemura M, Shibahara J, Takahashi M, Momose T, Saito N.
  • Journal Title: Brain Tumor Pathol Volume: 32 Pages: 210-215
  • DOI: 10.1007/s10014-014-0210-4
  • Peer Reviewed
• [Journal Article] Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment (2015)
  • Author(s): van Thuijl HF, Mazor T, Johnson BE, Fouse SD, Aihara K, Hong C, Malmström A, Hallbeck M, Heimans JJ, Kloezeman JJ, Stenmark-Askmalm M, Lamfers ML, Saito N, Aburatani H, Mukasa A, Berger MS, Söderkvist P, Taylor BS, Molinaro AM, Wesseling P, Reijneveld JC, Chang SM, Ylstra B, Costello JF
  • Journal Title: Acta Neuropathol Volume: 129 Pages: 597-604
  • DOI: 10.1007/s00401-015-1403-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 5hmC plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex (2014)
  • Author(s): Hiroki Takai, Tetsu Akiyama et al.
  • Journal Title: Cell Rep Volume: 9 Pages: 48-60
  • DOI: 10.1016/j.celrep.2014.08.071
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intracranial Germ Cell Tumor Genome Analysis Consortium (iGCT Consortium). Mutually exclusive mutations of KIT and RAS are associated with KIT mRNA expression and chromosomal instability in primary intracranial pure germinomas (2014)
  • Author(s): Fukushima S, Otsuka A, Suzuki T, Yanagisawa T, Mishima K. et al.
  • Journal Title: Acta Neuropathol Volume: 127 Pages: 911-925
  • DOI: 10.1007/s00401-014-1247-5
  • Peer Reviewed / Open Access
• [Journal Article] がんゲノムの多様性解析と治療への展開 (2014)
  • Author(s): 武笠晃丈
  • Journal Title: 実験医学 Volume: 32 Pages: 1928-1935
• [Journal Article] がんの進展・治療に伴うゲノム変化 (2014)
  • Author(s): 武笠晃丈
  • Journal Title: 医学のあゆみ Volume: 249 Pages: 1099-1104
• [Presentation] 遺伝子プロファイル解析から考える神経膠腫の診断と治療戦略 (2016)
  • Author(s): 武笠晃丈
  • Organizer: Temozolomide Forum in HIROSHIMA 2016
  • Place of Presentation: リーガロイヤルホテル広島（広島県・広島市）
  • Year and Date: 2016-12-13
  • Invited
• [Presentation] Molecular pathological analysis on IDH-wildtype adult low-grade gliomas (2016)
  • Author(s): Akitake Mukasa, Koki Aihara, Genta Nagae, Junji Shibahara, Shota Tanaka, Shunsaku Takayanagi, Masashi Nomura, Motoo Nagane, Yoshitaka Narita, Keisuke Ueki, Ryo Nishikawa, Hiroyuki Aburatani, Nobuhito Saito
  • Organizer: 21th Annual Meeting of the Society of Neuro-Oncology
  • Place of Presentation: Farimont Scottsdate Princess Hotel (Scottsdale, Arizona, USA)
  • Year and Date: 2016-11-19
  • Int'l Joint Research
• [Presentation] Influence of anticancer therapy on clonal evolution and intratumoral heterogeneity of gliomas (2016)
  • Author(s): Akitake Mukasa
  • Organizer: 75rd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-08
  • Invited
• [Presentation] 再発神経膠腫の分子遺伝学的変化に基づく治療戦略の構築 (2016)
  • Author(s): 武笠晃丈、相原功輝、齊藤邦昭、永江玄太、野村昌志、根城 尭英、高柳俊作、田中將太、柳澤 俊介、高橋 慧、西川亮、永根基雄、成田善孝、植木敬介、油谷浩幸、斉藤延人
  • Organizer: 第75回日本脳神経外科学会
  • Place of Presentation: 福岡国際会議（福岡県・福岡市）
  • Year and Date: 2016-09-30
• [Presentation] グリオーマのゲノム多様性とクローン進化に及ぼす抗がん治療の影響 (2016)
  • Author(s): 武笠晃丈
  • Organizer: 第21回脳腫瘍の外科学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京都・港区）
  • Year and Date: 2016-09-09
  • Invited
• [Presentation] マルチオミクス解析からみたグリオーマの多様性とその治療における意義 (2016)
  • Author(s): 武笠晃丈
  • Organizer: 先端脳腫瘍治療シンポジウム 2016
  • Place of Presentation: MSD株式会社 仙台事務所（宮城県・仙台市）
  • Year and Date: 2016-06-01
  • Invited
• [Presentation] A multidisciplinary approach to the treatment of brain tumor. (2016)
  • Author(s): 武笠晃丈, 斉藤延人
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸コンベンションセンター（兵庫県・神戸市）
  • Year and Date: 2016-05-18
  • Invited
• [Presentation] Genome-wide methylation analysis identifies genomic DNA demethylation during malignant progression of gliomas (2016)
  • Author(s): Akitake Mukasa, Kuniaki Saito, Koki Aihara, Genta Nagae, Shota Tanaka, Yoshitaka Narit, Keisuke Ueki, Ryo Nishikawa, Motoo Nagane, Hiroyuki Aburatani, Nobuhito Saito.
  • Organizer: 21st International Conference on Brain Tumor Research and Therapy
  • Place of Presentation: 万国津梁館（沖縄県・名護市）
  • Year and Date: 2016-04-12
  • Int'l Joint Research / Invited
• [Presentation] 9.IDH遺伝子変異を有さない成人びまん性低悪性度神経膠腫の分子病理学的解析 (2015)
  • Author(s): 武笠晃丈、相原功輝、高柳俊作、田中將太、野村昌志、柳澤俊介、永江玄太、上田宏生、山本尚吾、辰野健二、白畑充章、植木敬介、永根基雄、成田善孝、市村幸一、柴原純二、小森隆司、西川 亮、油谷浩幸、斉藤延人
  • Organizer: 第33回日本脳腫瘍学会
  • Place of Presentation: 京都
  • Year and Date: 2015-12-07
• [Presentation] 神経膠腫の悪性化とケノム進化一新たな治療法開発へ (2015)
  • Author(s): 武笠晃丈
  • Organizer: 第53回日本癌治療学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2015-10-30
  • Invited
• [Presentation] 神経膠腫の時間的・空間的な多様性からみた治療戦略の展望 (2015)
  • Author(s): 武笠晃丈
  • Organizer: 第74回日本脳神経外科学会
  • Place of Presentation: 札幌市
  • Year and Date: 2015-10-14
  • Invited
• [Presentation] グリオーマの遺伝子診断と治療戦略 (2015)
  • Author(s): 武笠晃丈
  • Organizer: 第16回日本分子脳神経外科学会
  • Place of Presentation: 浜松市
  • Year and Date: 2015-08-28
  • Invited
• [Presentation] Clonal Evolution and Intratumoral Heterogeneity of Glioma (2015)
  • Author(s): Akitake Mukasa
  • Organizer: The 1st TGU Medical Symposium of The University of Chicago The University of Tokyo
  • Place of Presentation: 東京
  • Year and Date: 2015-06-30
  • Int'l Joint Research / Invited
• [Presentation] ゲノム解析から考える低悪性度神経膠腫の治療戦略の問題点 (2015)
  • Author(s): 武笠晃丈
  • Organizer: 第２９回東京脳腫瘍治療懇話会
  • Place of Presentation: 東京
  • Year and Date: 2015-06-19
  • Invited
• [Presentation] DNA methylation profile analysis of gliomas revealed a change in methylation status during malignant progression (2015)
  • Author(s): Akitake Mukasa, Kuniaki Saito, Koki Aihara, Genta Nagae, Mayu Omata, Rhyohei Otani, Shunsaku Takayanagi, Shota Tanaka, Yoshitaka Narita, Yoshitaka Narita, Keisuke Ueki, Ryo Nishikawa, Motoo Nagane, Hiroyuki Aburatani, Nobuhito Saito
  • Organizer: American Association for Cancer Research(AACR) Annual Meeting 2015
  • Place of Presentation: Philadelphia
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] 神経膠腫悪性転化症例のオミクス解析から考える個別化治療戦略 (2014)
  • Author(s): 武笠 晃丈、齊藤 邦昭、相原 功輝、永江 玄太、Johnson BE、高柳 俊作、大谷 亮平、田中 將太、柳澤 俊介、上田 宏生、山本 尚吾、辰野 健二、Costello JF、西川 亮、永根 基雄、成田 善孝、植木 敬介、油谷 浩幸、斉藤 延人
  • Organizer: 第32回日本脳腫瘍学会学術集会
  • Place of Presentation: 浦安
  • Year and Date: 2014-11-30 – 2014-12-02
• [Presentation] グリオーマの発生・進展にかかわるエピゲノム異常 (2014)
  • Author(s): 武笠 晃丈
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] グリオーマの腫瘍内多様性に及ぼす抗がん治療の影響 (2014)
  • Author(s): 武笠 晃丈
  • Organizer: 第87回日本生化学大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] 化学療法剤による神経膠腫ゲノム不安定性の加速の可能性 (2014)
  • Author(s): 武笠 晃丈、相原 功輝、齊藤 邦昭、Johnson BE、高柳 俊作、上田 宏生、山本 尚吾、辰野 健二、永江 玄太、成田 善孝、永根 基雄、西川 亮、植木 敬介、Costello JF、油谷 浩幸、斉藤 延人
  • Organizer: 第73回日本脳神経外科学会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] Clonal evolution of glioma induced by anti-cancer therapy (2014)
  • Author(s): 武笠 晃丈
  • Organizer: 第73回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] グリオーマゲノム解析がもたらす治療戦略構築へのヒント (2014)
  • Author(s): 武笠 晃丈
  • Organizer: 第19回 北海道脳腫瘍治療研究会
  • Place of Presentation: 札幌
  • Year and Date: 2014-07-05
  • Invited
• [Presentation] 化学療法がもたらすがんゲノム不安定性の加速 (2014)
  • Author(s): 武笠 晃丈
  • Organizer: 第18回 日本がん分子標的治療学会
  • Place of Presentation: 仙台
  • Year and Date: 2014-06-26 – 2014-06-27
  • Invited
• [Presentation] ゲノム解析により明らかとなる神経膠腫の多様性と、その治療・悪性化にかかわる問題点 (2014)
  • Author(s): 武笠 晃丈
  • Organizer: 第9回 脳腫瘍の基礎シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2014-04-26
  • Invited
• [Book] 上衣系腫瘍, グリオーマ治療のDecision Making 脳神経外科診療プラクティス (2016)
  • Author(s): 武笠晃丈
  • Total Pages: 4
  • Publisher: 文光堂
• [Book] 脳腫瘍の部位別発症頻度と問題点, 脳腫瘍学 日本臨床 2016年9月増刊号 (2016)
  • Author(s): 武笠晃丈、田中將太、斉藤延人
  • Total Pages: 5
  • Publisher: 日本臨床社