Intraoperative rapid and sensitive detection of genetic alterations in lower-grade gliomas

• Project/Area Number: 17K16643
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Nagoya University
• Principal Investigator: AOKI KOSUKE 名古屋大学, 医学系研究科, 特任助教 (10759773)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 低悪性度神経膠腫 / 遺伝子診断 / 神経膠腫 / 遺伝子異常 / 術中迅速診断 / 術中診断

Outline of Final Research Achievements

The classification of lower-grade glioma (LGG) are based on not only pathological diagnosis, but also genetic alterations: the presence or absence of IDH mutation and 1p/19q co-deletion. Since the ATRX mutation is mutually exclusive with the 1p/19q co-deletion, it has been suggested that it could serve as a surrogate marker for genotyping of LGG. In this study, we performed immunostaining against ATRX on 78 cases of LGG with a known genetic background. Then the genetic classification was misjudged in 14% of tumors if ATRX mutation was used as a surrogate marker. We reported that ATRX mutation alone was not suitable for genotyping of LGG (Yamamichi et al, Brain Tumor Pathology, 2018). In the future, more accurate and simple genetic diagnostic methods are desired.

Academic Significance and Societal Importance of the Research Achievements

LGGは、その遺伝学的分類により生命予後が大きく異なる。また現在、遺伝学的分類毎の治療法も提唱されており、正確な診断は、患者の正確な予後予測と治療法選択にますます重要性を増してくると思われる。今回、比較的簡便に計測可能なATRXの免疫染色法による分類では、LGGの14%で誤った診断を下してしまうことを明らかにしている。本研究成果は、LGGの正確な遺伝子分類法を考える上で、大きな役割を果たす結果が得られたと考えられる。

Research Products

• [Journal Article] H3F3A mutant allele specific imbalance in an aggressive subtype of diffuse midline glioma, H3 K27M-mutant. (2020)
  • Author(s): Maeda S, Ohka F, Okuno Y, Aoki K, Motomura K, Takeuchi K, Kusakari H, Yanagisawa N, Sato S, Yamaguchi J, Tanahashi K, Hirano M, Kato A, Shimizu H, Kitano Y, Yamazaki S, Yamashita S, Takeshima H, Shinjo K, Kondo Y, Wakabayashi T, Natsume A.
  • Journal Title: Acta Neuropathologica Communications Volume: 8 Issue: 1 Pages: 8-19
  • DOI: 10.1186/s40478-020-0882-4
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma (2019)
  • Author(s): Ranjit Melissa、Hirano Masaki、Aoki Kosuke、Okuno Yusuke、Ohka Fumiharu、Yamamichi Akane、Kato Akira、Maeda Sachi、Motomura Kazuya、Matsuo Keitaro、Enomoto Atsushi、Ino Yasushi、Todo Tomoki、Takahashi Masahide、Wakabayashi Toshihiko、Kato Takuya、Natsume Atsushi
  • Journal Title: Cell Reports Volume: 26 Issue: 9 Pages: 2274-2281
  • DOI: 10.1016/j.celrep.2019.01.109
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Overview of DNA methylation in adult diffuse gliomas (2019)
  • Author(s): Aoki Kosuke、Natsume Atsushi
  • Journal Title: Brain Tumor Pathology Volume: 36 Issue: 2 Pages: 84-91
  • DOI: 10.1007/s10014-019-00339-w
  • Peer Reviewed
• [Journal Article] A novel high-sensitivity assay to detect a small fraction of mutant IDH1 using droplet digital PCR (2018)
  • Author(s): Hirano Masaki、Ohka Fumiharu、Maeda Sachi、Chalise Lushun、Yamamichi Akane、Aoki Kosuke、Kato Akira、Tanahashi Kuniaki、Motomura Kazuya、Nishimura Yusuke、Hara Masahito、Shinjo Keiko、Kondo Yutaka、Wakabayashi Toshihiko、Natsume Atsushi
  • Journal Title: Brain Tumor Pathology Volume: - Issue: 2 Pages: 97-105
  • DOI: 10.1007/s10014-018-0310-7
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemical ATRX expression is not a surrogate for 1p19q codeletion (2018)
  • Author(s): Yamamichi Akane、Ohka Fumiharu、Aoki Kosuke、Suzuki Hiromichi、Kato Akira、Hirano Masaki、Motomura Kazuya、Tanahashi Kuniaki、Chalise Lushun、Maeda Sachi、Wakabayashi Toshihiko、Kato Yukinari、Natsume Atsushi
  • Journal Title: Brain Tumor Pathology Volume: - Issue: 2 Pages: 106-113
  • DOI: 10.1007/s10014-018-0312-5
  • NAID: 120006496406
  • Peer Reviewed
• [Journal Article] Prognostic relevance of genetic alterations in diffuse lower-grade gliomas (2017)
  • Author(s): Aoki Kosuke、Nakamura Hideo、Suzuki Hiromichi et al.
  • Journal Title: Neuro-Oncology Volume: 20 Issue: 1 Pages: 66-77
  • DOI: 10.1093/neuonc/nox132
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of perivascular tumour cells defined by CD109 expression in progression of glioma (2017)
  • Author(s): Shiraki Yukihiro、Mii Shinji、Enomoto Atsushi、Momota Hiroyuki、Han Yi-Peng、Kato Takuya、Ushida Kaori、Kato Akira、Asai Naoya、Murakumo Yoshiki、Aoki Kosuke、Suzuki Hiromichi、Ohka Fumiharu、Wakabayashi Toshihiko、Todo Tomoki、Ogawa Seishi、Natsume Atsushi、Takahashi Masahide
  • Journal Title: The Journal of Pathology Volume: 243 Issue: 4 Pages: 468-480
  • DOI: 10.1002/path.4981
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel all-in-one intraoperative genotyping system for IDH1-mutant glioma. (2017)
  • Author(s): Ohka F, Yamamichi A, Kurimoto M, Motomura K, Tanahashi K, Suzuki H, Aoki K, Deguchi S, Chalise L, Hirano M, Kato A, Nishimura Y, Hara M, Kato Y, Wakabayashi T, Natsume A.
  • Journal Title: Brain Tumor Pathol. Volume: 印刷中 Issue: 2 Pages: 91-97
  • DOI: 10.1007/s10014-017-0281-0
  • NAID: 120006331835
  • Peer Reviewed
• [Presentation] 低悪性度神経膠腫における遺伝子異常の全貌 (2018)
  • Author(s): 青木恒介
  • Organizer: 第１９回日本分子脳神経外科学会
  • Invited
• [Presentation] Classification and grading of diffuse astrocytic tumors (2018)
  • Author(s): Kosuke Aoki
  • Organizer: The 5th International Symposium of Brain Tumor Pathology
  • Int'l Joint Research / Invited
• [Presentation] グレードII, IIIグリオーマの分子診断におけるATRX免疫組織染色は 1p/19q共欠失解析のサロゲートとして有用か？ (2017)
  • Author(s): 山道 茜, 大岡 史治, 青木 恒介, 加藤 彰, Melissa Ranjit, Chalise Lushun, 平野 雅規, 棚橋 邦明, 本村 和也, 松原 年生, 鈴木 秀謙, 若林 俊彦, 加藤 幸成, 夏目 敦至
  • Organizer: 第76回日本脳神経外科学会学術総会
• [Presentation] Mathematic model of tumor development and malignant transformation in WHO grade II diffuse glioma (2017)
  • Author(s): 青木恒介、山本高士、山本君代、鈴木啓道、大岡史治、Melissa Ranjit、本村和也、中村英夫、成田善孝、高橋雅道、吉本幸司、籾井泰朋、村垣善浩、若林俊彦、波江野洋、夏目敦至
  • Organizer: 第76回日本脳神経外科学会学術総会
• [Presentation] 放射線や化学療法がWHO grade IIびまん性神経膠腫の腫瘍進展と悪性転化に与える影響 (2017)
  • Author(s): 青木恒介、山本高士、山本君代、鈴木啓道、大岡史治、Melissa Ranjit、本村和也、中村英夫、成田善孝、高橋雅道、吉本幸司、籾井泰朋、村垣善浩、若林俊彦、波江野洋、夏目敦至
  • Organizer: 第35回日本脳腫瘍学会学術集会
• [Book] がん転移学（上）-がん転移のメカニズムと治療戦略:その基礎と臨床- （19）中枢神経系腫瘍の分子機構 (2017)
  • Author(s): 青木恒介、鈴木啓道、大岡史治、夏目敦至、小川誠司
  • Total Pages: 305
  • Publisher: 日本臨床
• [Remarks] 名古屋大学大学院医学系研究科 脳神経外科学
  • URL: https://med-nagoya-neurosurgery.jp/