Development of non-invasive novel diagnostic methods for primary central nervous system lymphoma using liquid biopsy for nucleic acids derived from cerebrospinal fluid

• Project/Area Number: 17K10873
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Kyorin University
• Principal Investigator: Shiokawa Yoshiaki 杏林大学, 医学部, 教授 (20245450)
• Co-Investigator(Kenkyū-buntansha): 市村 幸一 国立研究開発法人国立がん研究センター, 研究所, 分野長 (40231146)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 中枢神経系原発悪性リンパ腫 / Liquid biopsy / MYD88 / CD79B / 中枢神経系悪性リンパ腫 / liquid biopsy / cell free DNA / cellular DNA / Cell free DNA / CD79b / リキッドバイオプシー / 遺伝子解析 / 髄液 / 分子マーカー

Outline of Final Research Achievements

In this study, we aimed to establish a diagnostic method for detecting MYD88 and CD79B mutations, which are frequently mutated in PCNSL, from DNA in CSF. DNA was extracted from the CSF of 42 PCNSL cases, the optimal test conditions for the MYD88 mutation detection using digital PCR were established, and the test accuracy was verified. When the Target/Total value of 0.25% was set as the cutoff using the optimum amount of DNA yield in CSF, the sensitivity was 92.2% and the specificity was 100%, showing extremely high test accuracy. For the CD79B mutation, we are developing a diagnostic method by the qPCR.

Academic Significance and Societal Importance of the Research Achievements

本研究で定めた検査条件では、髄液中DNAに対するdigital PCR法を用いたMYD88 L265P変異検出法は非常に高い検査精度であった。MYD88変異またはCD79B変異を有する症例はPCNSL全体の約9割に上り(Nakamura T, Neuropathol Appl Neurobiol 42(3): 279-90, 2016)、本検査法の確立によりPCNSL患者の大半で生検術を回避できる可能性がある。迅速かつ低侵襲な確定診断の達成により、生検術困難な患者への適切な治療介入、身体的活動度の維持、QOL向上、ひいては現病の予後改善にも寄与することが期待される。

Research Products

• [Journal Article] Consecutive single-institution case series of primary central nervous system lymphoma treated by R-MPV or high-dose methotrexate monotherapy (2020)
  • Author(s): Sasaki N, Kobayashi K, Saito K, Shimizu S, Suzuki K, Lee J, Yamagishi Y, Shibahara J, Takayama N, Shiokawa Y, Nagane M
  • Journal Title: Jpn J Clin Oncol Volume: inpress Issue: 9 Pages: 1-11
  • DOI: 10.1093/jjco/hyaa073
  • Peer Reviewed
• [Journal Article] Multiagent immunochemotherapy, R-MPV-A, for patients with secondary central nervous system lymphoma (2019)
  • Author(s): Nagane M, Kobayashi K, Saito K, Shimada D, Matsumoto Y, Iijima S, Sasaki N, Yamagishi Y, Takayama N, Shiokawa Y
  • Journal Title: Neuro-Oncology Advances Volume: 1 Issue: Supplement_2 Pages: ii32-ii32
  • DOI: 10.1093/noajnl/vdz039.145
  • Peer Reviewed
• [Journal Article] MyD88 Mutation in Elderly Predicts Poor Prognosis in Primary Central Nervous System Lymphoma: Multi-Institutional Analysis (2018)
  • Author(s): Takano Shingo、Hattori Keiichiro、Ishikawa Eiichi、Narita Yoshitaka、Iwadate Yasuo、Yamaguchi Fumio、Nagane Motoo、Akimoto Jiro、Oka Hidehiro、Tanaka Satoshi、Sakata Mamiko、Matsuda Masahide、Yamamoto Tetsuya、Chiba Shigeru、Matsumura Akira
  • Journal Title: World Neurosurgery Volume: 112 Pages: e69-e73
  • DOI: 10.1016/j.wneu.2017.12.028
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide DNA methylation profiles identifies primary central nervous system lymphomas as a distinct entity from systemic diffuse large B-cell lymphomas (2017)
  • Author(s): Nakamura T, Yamashita S, Fukumura K, Tanaka K, Nagane M, Narita Y, Mano H, Ushijima T, Ichimura K
  • Journal Title: Acta Neuropathol Volume: 133 Issue: 2 Pages: 321-324
  • DOI: 10.1007/s00401-016-1664-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic factors for primary central nervous system lymphomas treated with high-dose methotrexate-based chemo-radiotherapy (2017)
  • Author(s): Lee Jeunghun、Shishido-Hara Yukiko、Suzuki Kaori、Shimizu Saki、Kobayashi Keiichi、Kamma Hiroshi、Shiokawa Yoshiaki、Nagane Motoo
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 47 Issue: 10 Pages: 925-934
  • DOI: 10.1093/jjco/hyx098
  • Peer Reviewed / Open Access
• [Presentation] 中枢神経系悪性リンパ腫における髄液特異的遺伝子変異検出による液性診断の有用性 (2020)
  • Author(s): 山岸夢希、佐々木重嘉、松下裕子、清水早紀、齊藤邦昭、小林啓一、塩川芳昭、永根基雄、市村幸一
  • Organizer: 日本脳神経外科学会 第79回学術総会
• [Presentation] 中枢神経系悪性リンパ腫における髄液特異的遺伝子変異検出による液性診断の有用性 (2020)
  • Author(s): 山岸夢希、佐々木重嘉、松下裕子、清水早紀、齊藤邦昭、小林啓一、成田善孝、塩川芳昭、永根基雄、市村幸一
  • Organizer: 第38回 日本脳神経外科学会学術集会
• [Presentation] 二次性中枢神経系悪性リンパ腫に対するR-MPV-A療法の治療成績 (2019)
  • Author(s): 永根基雄，小林啓一，齊藤邦昭，島田大輔，松本淑恵，飯島昌平，佐々木重嘉，山岸夢希，高山信之，塩川芳昭
  • Organizer: 第37回日本脳腫瘍学会学術集会
• [Presentation] 悪性脳腫瘍の治療開発：神経膠腫・悪性リンパ腫を主に (2018)
  • Author(s): 永根基雄
  • Organizer: 第10回三重脳腫瘍セミナー
  • Invited
• [Presentation] Efficacy and prognostic factors of combined immunochemotherapy R-MPV-A with reduced or deferred radiotherapy for patients with primary CNS lymphoma (2017)
  • Author(s): Motoo Nagane, Keiichi Kobayashi, Kuniaki Saito, Nobuyoshi Sasaki, Satoshi Kume, Yuki Yamagishi, Saki Shimizu, Kaori Suzuki, Yoshiaki Shiokawa
  • Organizer: 5th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies (WFNOS)
  • Int'l Joint Research
• [Presentation] Update on JCOG1114 for newly diagnosed PCNSL in Japan (2017)
  • Author(s): Motoo Nagane
  • Organizer: 2017 International PCNSL Collaborative Group Meeting
  • Int'l Joint Research