Why is neurofibromatosis type 2 formidable? Comparison between NF2-associated and sporadic schwannomas to analyze molecular mechanism

• Project/Area Number: 15K10340
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Fukushima Medical University
• Principal Investigator: Saito Kiyoshi 福島県立医科大学, 医学部, 教授 (00240804)
• Co-Investigator(Kenkyū-buntansha): 森 努 福島県立医科大学, 看護学部, 准教授 (60244373) ; 岩味 健一郎 愛知医科大学, 医学部, 講師 (80534841)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 神経線維腫症2型 / 髄膜腫 / 悪性髄膜腫 / 神経鞘腫 / 遺伝子発現解析 / 神経繊維腫症2型

Outline of Final Research Achievements

Neurofibromatosis type 2 (NF2) is an autosomal dominant inherited disease associated with multiple schwannomas and meningiomas in the nervous system. Although these tumors are usually benign, long-term outcome of NF2 is unfavorable. We compared RNA expression of NF2-associated schwannomas with sporadic schwannomas. We could not find significant difference in RNA expression patterns between them. We analyzed function of IGF2BP1 which was highly methylated in recurrent meningiomas. In HKBMM cells originated from human malignant meningioma, IGF2BP1 controlled cell adhesion through the function of Cadherin 11. Methylation of IGF2BP1 may contribute to the tumor recurrence by reducing cell adhesion and inducing cell migration.

Academic Significance and Societal Importance of the Research Achievements

神経線維腫症2型（NF2）は神経系に神経鞘腫や髄膜腫が多発する遺伝性疾患です。NF2の長期予後は不良ですので、治療指針の策定、全国での治療体制の構築などを行い、またベバシズマブ点滴治療の医師主導治験を計画して、予後の改善に務めています。一般にこれらの良性脳腫瘍は手術による摘出で治療しますが、再発したり悪性化したり治療困難なこともあります。NF2を研究することで、治療困難な良性脳腫瘍に対する新しい治療法開発に結びつくことが期待されます。

Research Products

• [Journal Article] Skull base invasive low-grade meningiomas, a distinct genetic subgroup: A microarray gene expression profile analysis. (2018)
  • Author(s): Sakuma J, Fujii M, Kishida Y, Iwami K, Oda K, Iwatate K, Ichikawa M, Bakhit M, Sato T, Waguri S, Watanabe S, Saito K
  • Journal Title: bioRxiv Volume: 0 Pages: 1-31
  • DOI: 10.1101/371716
• [Journal Article] Palliative shunt surgery for patients with leptomeningeal metastasis (2018)
  • Author(s): Murakami Y, Ichikawa M, Bakhit M, Jinguji S, Sato T, Fujii M, Sakuma J, Saito K
  • Journal Title: Clinical Neurology and Neurosurgery Volume: 168 Pages: 175-178
  • DOI: 10.1016/j.clineuro.2018.03.008
  • Peer Reviewed
• [Journal Article] Intraoperative Fluorescence Cerebral Angiography by Laser Surgical Microscopy: Comparison With Xenon Microscopy and Simultaneous Observation of Cerebral Blood Flow and Surrounding Structures (2018)
  • Author(s): Ito Y, Suzuki K, Ichikawa T, Watanabe Y, Sato T, Sakuma J, Saito K
  • Journal Title: Operative Neurosurgery Volume: 0 Issue: 6 Pages: 1-7
  • DOI: 10.1093/ons/opy159
  • Peer Reviewed
• [Journal Article] 神経線維腫症1型（レックリングハウゼン病）診療ガイドライン2018 (2018)
  • Author(s): 吉田雄一, 倉持 朗，太田有史，古村南夫，今福信一，松尾宗明，筑田博隆，舟崎裕記，齋藤 清，佐谷秀行，錦織千佳子
  • Journal Title: 日皮会誌 Volume: 128 Pages: 17-34
• [Journal Article] Population characteristics and progressive disability in neuofibromatosis type 2 (2017)
  • Author(s): Iwatate K, Yokoo T, Iwatate E, Ichikawa M, Fujii M, Sakuma J, Saito K
  • Journal Title: World Neurosurgery Volume: 106 Pages: 653-660
  • DOI: 10.1016/j.wneu.2017.07.036
  • Peer Reviewed / Open Access
• [Journal Article] Jugular foramen collision tumor (schwannoma and plasma cell pseudotumor), a probable IgG4-related disease (2017)
  • Author(s): Bakhit MS, Fujii M, Jinguji S, Sato T, Sakuma J, Saito K
  • Journal Title: World Neurosurgery Volume: 102
  • Peer Reviewed
• [Journal Article] Jugular foramen collision tumor (schwannoma and plasma cell pseudotumor), a probable IgG4-related disease: a case report (2017)
  • Author(s): Bakhit MS, Fujii M, Jinguji S, Sato T, Sakuma J, Saito K
  • Journal Title: World Neurosurgery Volume: in press Pages: 694.e9-694.e13
  • DOI: 10.1016/j.wneu.2017.03.142
  • Peer Reviewed / Open Access
• [Journal Article] Association of the SEL1L protein transmembrane domain with HRD1 ubiquitin ligase regulates ERAD-L (2016)
  • Author(s): Hoshikawa N, Wada I
  • Journal Title: FEBS Journal Volume: 283 Issue: 1 Pages: 157-172
  • DOI: 10.1111/febs.13564
  • Peer Reviewed / Open Access
• [Journal Article] 神経線維腫症II型 (2015)
  • Author(s): 齋藤 清，市川優寛，佐久間潤
  • Journal Title: Clinical Neuroscience Volume: 33 Pages: 455-458
• [Presentation] Our struggle for neurofibromatosis type 2 (2018)
  • Author(s): Saito K, Iwatate K, Ichikawa M, Nemoto M, Jinguji S, Yamada M, Kuromi Y, Sato T, Sakuma J, Watanabe T, Fujii M
  • Organizer: Joint Neurosurgical Convention 2018
  • Int'l Joint Research
• [Presentation] Partial debulking of tumor with orbital expansion to alleviate exophthalmos due to invasive spheno-orbital meningioma (2018)
  • Author(s): Nagai K, Hiruta R, Jinguji S, Nemoto M, Iwatate K, Ichikawa M, Sato T, Kojima T, Fujii M, Saito K
  • Organizer: 14th Asian-Oceanian International Congress on Skull Base Surgery
  • Int'l Joint Research
• [Presentation] 神経線維腫症2型の 聴神経腫瘍に対する アバスチン療法の現状 ‐医師主導治験の実現にむけて‐ (2018)
  • Author(s): 藤井正純, 齋藤 清
  • Organizer: あせび会神経線維腫症２型講演会
  • Invited
• [Presentation] 神経線維腫症２型に対する治療 (2018)
  • Author(s): 齋藤 清, 藤井正純, 岩楯兼尚, 山田昌幸, 黒見洋介, 佐藤祐介, 神宮字伸哉, 市川優寛, 佐藤 拓, 佐久間潤
  • Organizer: 第34回白馬脳神経外科セミナー
• [Presentation] 浸潤性髄膜腫による眼球突出に対し、眼位整復を目的とした眼窩拡大・腫瘍減量術を施行した一例 (2018)
  • Author(s): 蛭田 亮, 神宮字伸哉, 根本未緒, 岩楯兼尚, 市川優寛, 佐藤 拓, 小島隆生, 藤井正純, 佐久間 潤, 齋藤 清
  • Organizer: 第30回日本頭蓋底外科学会
• [Presentation] 悪性髄膜腫細胞HKBMM の過剰な遊走性に関わるIGF2BP1 の役割 (2018)
  • Author(s): 黒見洋介, 荒井斉祐, 鈴木貴久, 岸田悠吾, 和田郁夫, 齋藤 清
  • Organizer: 第77回社団法人日本脳神経外科学会総会
• [Presentation] NF2治療についてのアンケート調査：NF2治療体制構築に向けて (2018)
  • Author(s): 佐藤祐介, 齋藤 清
  • Organizer: 難治性疾患等政策研究事業「神経皮膚症候群に関する診療科横断的な診療体制の確立」班会議
• [Presentation] Our struggle for Neurofibromatosis type 2 (2018)
  • Author(s): Saito K, Iwatate K, Ichikawa M, Nemoto M, Jinguji S, Yamada M, Kuromi Y, Sato T, Sakuma J, Watanabe T, Fujii M
  • Organizer: The 8th International Mt.BANDAI Symposium for Neuroscience
  • Int'l Joint Research
• [Presentation] 神経線維腫症2型に対する治療 (2018)
  • Author(s): 齋藤 清, 藤井正純、岩楯兼尚、山田昌幸、黒見洋介、佐藤祐介、神宮字伸哉、市川優寛、佐藤 拓、佐久間潤
  • Organizer: 第34回白馬脳神経外科セミナー
• [Presentation] 神経線維腫症２型に対する治療：最適な治療は何か？ (2017)
  • Author(s): 齋藤 清, 藤井正純,岩楯兼尚, 山田昌幸, 黒見洋介, 村上友太, 古川佑哉, 神宮字伸哉, 市川優寛, 佐藤 拓, 佐久間潤
  • Organizer: 第26回日本聴神経腫瘍研究会
• [Presentation] 神経線維腫症2型に対する治療指針改定と最適な治療 (2017)
  • Author(s): 藤井正純, 齋藤 清
  • Organizer: 2017年度神経線維腫症2型医療講演会＆患者交流会
  • Invited
• [Presentation] 聴性脳幹インプラント（ABI）の施行経験 (2017)
  • Author(s): 蛭田 亮, 佐久間 潤, 小祝 萌, 長井健一郎, 根本未緒, 飯島綾子, 佐藤祐介, 岩楯兼尚, 神宮字伸哉, 市川優寛, 小島隆生, 藤井正純, 齋藤 清, 森田明夫
  • Organizer: 第81回福島脳神経外科談話会
• [Presentation] 神経線維腫症2型の治療：現状と課題 (2016)
  • Author(s): 藤井正純、岩楯兼尚、市川優寛、神宮字伸哉、佐藤 拓、佐久間潤、齋藤 清
  • Organizer: 第21回日本脳腫瘍の外科学会
  • Place of Presentation: 東京
  • Year and Date: 2016-09-09
  • Invited
• [Presentation] Microarray gene expression profiling of skull base invasive meningiomas (2016)
  • Author(s): Bakhit MS, Saito K, Sakuma J, Fujii M, Kishida Y, Iwami K, Oda K, Ichikawa M, Sato T, Waguri S, Watanabe S
  • Organizer: World Skull Base 2016
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2016-06-14
  • Int'l Joint Research
• [Presentation] Evaluation of clinical factors of NF2 from nationwide registry data in Japan (2016)
  • Author(s): Iwatate K, Saito K, Yokoo T, Iwatate E, Sakuma J, Fujii M, Ichikawa M, Sato T, Kishida Y, Jinguji S
  • Organizer: World Skull Base 2016
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2016-06-14
  • Int'l Joint Research
• [Presentation] One-stage removal of sphenoorbital, convexity and ventricular meningiomas in NF2 (2016)
  • Author(s): Iijima A, Fujii M, Kuromi Y, Yamada M, Murakami Y, Jinguji S, Iwatate K, Sato T, Sakuma J, Saito K
  • Organizer: World Skull Base 2016
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2016-06-14
  • Int'l Joint Research
• [Presentation] Treatment of neurofibromatosis type 2 patients with analysis nationwide registry data in Japan (2016)
  • Author(s): Sakuma J, Iwatate K, Ichikawa M, Sato T, Kishida Y, Oda K, Jinguji S, Fujii M, Saito K
  • Organizer: 5th Mt. Bandai & PPNC 2016
  • Place of Presentation: Phnom Penh, Cambodia
  • Year and Date: 2016-04-07
  • Int'l Joint Research
• [Presentation] 神経線維腫症2型に対する治療方針の提案 (2016)
  • Author(s): 齋藤 清、岩楯兼尚、山田昌幸、黒見洋介、村上友太、古川佑哉、神宮字伸哉、織田惠子、岸田悠吾、市川優寛、佐藤 拓、藤井正純、佐久間潤
  • Organizer: 第25回日本聴神経腫瘍研究会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 神経線維腫症2型に対する治療方針の提案 (2015)
  • Author(s): 齋藤 清、市川優寛、岩楯兼尚、佐藤 拓、岸田悠吾、織田惠子、岩味健一郎、神宮字伸哉、山田昌幸、黒見洋介、村上友太、古川佑哉、佐久間潤
  • Organizer: 第74回社団法人日本脳神経外科学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2015-10-14
• [Presentation] 国内における神経線維腫症2型の現状：臨床調査個人票の解析から (2015)
  • Author(s): 岩楯兼尚、齋藤 清、古川祐哉、山田昌幸、岩味健一郎、神宮字伸哉、岸田悠吾、市川優寛、佐藤 拓、佐久間潤
  • Organizer: 第25回日本脳腫瘍の外科学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-09-25
• [Book] 最新遺伝性腫瘍・家族性腫瘍と遺伝カウンセリング (2016)
  • Author(s): 齋藤 清
  • Total Pages: 5
  • Publisher: メディカルドゥ
• [Book] 日本臨牀増刊号 家族性腫瘍学：家族性腫瘍の最新研究動向「Neurofibromatosis type 2（神経線維腫症2型）」 (2015)
  • Author(s): 齋藤 清，市川優寛，佐久間潤
  • Total Pages: 607
  • Publisher: 日本臨牀社