Mechanistic insight into malignant transformation and therapeutic strategies based on the comparative multi-omics analysis of primary and recurrent gliomas
Project/Area Number |
26293321
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Partial Multi-year Fund |
Section | 一般 |
Research Field |
Neurosurgery
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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)
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Co-Investigator(Kenkyū-buntansha) |
田中 將太 東京大学, 医学部附属病院, 助教 (80643725)
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Co-Investigator(Renkei-kenkyūsha) |
SAITO Kuniaki 杏林大学, 医学部, 助教 (50446564)
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Project Period (FY) |
2014-04-01 – 2018-03-31
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Project Status |
Completed (Fiscal Year 2017)
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Budget Amount *help |
¥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)
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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.
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Report
(5 results)
Research Products
(56 results)
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[Journal Article] Differences in genetic and epigenetic alterations between von Hippel-Lindau disease-related and sporadic hemangioblastomas of the central nervous system.2017
Author(s)
Takayanagi S, Mukasa A, Tanaka S, Nomura M, Omata M, Yanagisawa S, Yamamoto S, Ichimura K, Nakatomi H, Ueki K, Aburatani H, Saito N
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Journal Title
Neuro Oncol.
Volume: 印刷中
Issue: 9
Pages: 1-7
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Distinct molecular profile of diffuse cerebellar gliomas2017
Author(s)
Nomura M, Mukasa A, Nagae G, Yamamoto S, Tatsuno K, Ueda H, Fukuda S, Umeda T, Suzuki T, Otani R, Kobayashi K, Maruyama T, Tanaka S, Takayanagi S, Nejo T, Takahashi S, Ichimura K, Nakamura T, Muragaki Y, Narita Y, Nagane M, Ueki K, Nishikawa R, Shibahara J, Aburatani H, Saito N
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Journal Title
Acta Neuropathologica
Volume: 134
Issue: 6
Pages: 941-956
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Identification of a novel fusion gene HMGA2-EGFR in glioblastoma2017
Author(s)
Komuro Akiyoshi、Raja Erna、Iwata Caname、Soda Manabu、Isogaya Kazunobu、Yuki Keiko、Ino Yasushi、Morikawa Masato、Todo Tomoki、Aburatani Hiroyuki、Suzuki Hiromichi、Ranjit Melissa、Natsume Atsushi、Mukasa Akitake、Saito Nobuhito、Okada Hitoshi、Mano Hiroyuki、Miyazono Kohei、Koinuma Daizo
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Journal Title
International Journal of Cancer
Volume: 142
Issue: 8
Pages: 1627-1639
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] 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
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Journal Title
Acta Neuropathol Commun.
Volume: 5
Issue: 1
Pages: 18-18
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A prospective, multicentre, single-arm clinical trial of bevacizumab for patients with surgically untreatable, symptomatic brain radiation necrosis2016
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.
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Journal Title
Neuro-Oncology Practice
Volume: 0
Issue: 4
Pages: 1-9
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
Acta Neuropathol Commun.
Volume: 4
Issue: 1
Pages: 79-79
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma2016
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.
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Journal Title
Neuro Oncol
Volume: 18(11)
Pages: 1559-1568
DOI
Related Report
Peer Reviewed
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[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
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Journal Title
Acta Neuropathol
Volume: Epub
Related Report
Peer Reviewed
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[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
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Journal Title
Acta Neuropathol.
Volume: 129
Issue: 4
Pages: 597-607
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Presentation] Genetic and epigenetic stability of oligodendrogliomas at recurrence2017
Author(s)
Akitake Mukasa, Koki Aihara, Masashi Nomura, Shota Tanaka, Junji Shibahara, Yoshitaka Narita, Motoo Nagane, Ryo Nishikawa, Keisuke Ueki, Hiroyuki Aburatani, Nobuhito Saito
Organizer
The 14th Meeting of the Asian Society for Neuro-Oncology
Related Report
Int'l Joint Research
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[Presentation] Characteristic molecular profile changes in primary and recurrent gliomas depending on their histopathology2017
Author(s)
Akitake Mukasa, Masashi Nomura, Kuniaki Saito, Koki Aihara, Genta Nagae, Takahide Nejo, Shota Tanaka, Shunsaku Takayanagi, Satoshi Takahashi, Mayu Omata, Taishi Nakamura, Yoshitaka Narita, Yoshihiro Muragaki, Motoo Nagane, Keisuke Ueki, Ryo Nishikawa, Hiroyuki Aburatani, Nobuhito Saito
Organizer
22nd Annual Meeting of the Society of Neuro-Oncology
Related Report
Int'l Joint Research
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[Presentation] Integrated and comparative multi-omics analysis of primary and recurrent glioma and its clinical application2017
Author(s)
Akitake Mukasa, Masashi Nomura, Kuniaki Saito, Koki Aihara, Genta Nagae, Takahide Nejo, Shunsaku Takayanagi, Shota Tanaka, Taishi Nakamura, Yoshitaka Narita, Yoshihiro Muragaki, Motoo Nagane, Keisuke Ueki, Ryo Nishikawa, Hiroyuki Aburatani, Nobuhito Saito
Organizer
第76回日本脳神経外科学会
Related Report
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[Presentation] Molecular pathological analysis on IDH-wildtype adult low-grade gliomas2016
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
Related Report
Int'l Joint Research
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[Presentation] Genome-wide methylation analysis identifies genomic DNA demethylation during malignant progression of gliomas2016
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
Related Report
Int'l Joint Research / Invited
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[Presentation] DNA methylation profile analysis of gliomas revealed a change in methylation status during malignant progression2015
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
Related Report
Int'l Joint Research
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