Evaluation of genetic factors for drug sensitivity in childhood leukemia by genome wide association analysis

• Project/Area Number: 15K18932
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Medical pharmacy
• Research Institution: Kitasato University
• Principal Investigator: Yoichi Tanaka 北里大学, 薬学部, 講師 (40525341)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ゲノムワイド関連解析 / 抗悪性腫瘍薬 / 小児急性リンパ性白血病 / 感受性 / 6-メルカプトプリン / 薬剤感受性 / 遺伝要因 / 小児白血病 / L-アスパラギナーゼ / 毒性 / 遺伝子多型 / メトトレキセート / 有害事象

Outline of Final Research Achievements

The treatment for childhood acute lymphoblastic leukemia treatment is used combined several anti-cancer drugs. We analyzed the association between genetic variants and the therapy related clinical information, which are drug-induced toxicities, allergy and drug concentration, by genome wide association study (GWAS). We found that 6-MP tolerability during maintenance therapy was significantly associated with the genetic variation of MED4 and NUDT15, and NEGR1 was possible association factor of tolerability. The MTHFR variant was possible association factor of delaying methotrexate level after high dose methotrexate treatment.

Research Products

• [Journal Article] Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia (2018)
  • Author(s): Tanaka Y, Nakadate H, Kondoh K, Nakamura K, Koh K, Manabe A
  • Journal Title: The Pharmacogenomics Journal Volume: 18 Issue: 2 Pages: 275-280
  • DOI: 10.1038/tpj.2017.12
  • Peer Reviewed
• [Journal Article] Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese (2018)
  • Author(s): Urayama Kevin Y.、Takagi Masatoshi、Kawaguchi Takahisa、Matsuo Keitaro、Tanaka Yoichi、Ayukawa Yoko、Arakawa Yuki、Hasegawa Daisuke、Yuza Yuki、Kaneko Takashi、Noguchi Yasushi、Taneyama Yuichi、Ota Setsuo、Inukai Takeshi、Yanagimachi Masakatsu、Keino Dai、Koike Kazutoshi、Toyama Daisuke、Inazawa Johji 他16名
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 789-789
  • DOI: 10.1038/s41598-017-19127-7
  • Peer Reviewed / Open Access
• [Presentation] NUDT15 ハプロタイプの6-メルカプトプリン感受性への影響 (2018)
  • Author(s): 田中庸一、近藤健介、康 勝好、尾鳥勝也、真部 淳
  • Organizer: 日本薬学会第138年会
• [Presentation] The association between plasma methotrexate concentration and genetic variant in high-dose methotrexate therapy for childhood acute lymphoblastic leukemia (2017)
  • Author(s): Yoichi Tanaka, Kevin Urayama, Makiko Mori, Daisuke Hasegawa, Koshi Akahane, Setsuo Ota, Katsuyoshi Koh, Atsushi Manabe
  • Organizer: 第５９回日本小児血液・がん学会学術集会
• [Presentation] 日本人小児ALLのL-アスパラギナーゼアレルギー発現におけるNFATC2 rs6021191多型の影響 (2016)
  • Author(s): 田中庸一、Kevin Urayama、森麻希子、長谷川大輔、石丸紗恵、寺田和樹、柳町昌克、太田節雄、高橋浩之、外山大輔、慶野 大、森脇浩一、高木正稔、藤村純也、関中悠仁、中村こずえ、佐藤雄也、小原 明、康 勝好、真部 淳
  • Organizer: 第58回日本小児血液・がん学会学術集会
  • Place of Presentation: 品川プリンスホテル（東京都港区）
  • Year and Date: 2016-12-15
• [Presentation] The association between L-asparaginase hypersensitivity and genetic variants in Japanese childhood ALL patients (2016)
  • Author(s): Tanaka Y, Urayama KY, Kawaguchi T, Mori M, Hasegawa D, Ishimaru S, Taneyama Y, Terada K, Yanagimachi M, Ota S, Takahashi H, Inukai T, Toyama D, Keino D, Moriwaki K, Takagi M, Fujimura J, Sekinaka Y, Nakamura K, Sato Y et al
  • Organizer: ASH annual meeting 2016
  • Place of Presentation: サンディエゴ（アメリカ合衆国）
  • Year and Date: 2016-12-03
  • Int'l Joint Research