Comprehensive analysis of gene mutations for precision medicine in pediatric acute myeloid leukemia

• Project/Area Number: 19K21333
• Project/Area Number (Other): 18H06234 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0904:Internal medicine of the bio-information integration and related fields
• Research Institution: Gunma Institute of Public Health and Environmental Sciences
• Principal Investigator: Genki Yamato 群馬県衛生環境研究所, 研究企画係, 研究員 (90825720)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 急性骨髄性白血病 / 小児 / 遺伝子異常 / AML / pediatrics / PTPN11 / プレシジョンメディスン / 網羅的変異解析 / 変異解析 / クリニカルシーケンス

Outline of Research at the Start

小児AML患者の30%以上が予後不良であるため、これまで申請者らは小児AMLの予後改善に寄与するべく、次世代シーケンサーで標的シーケンスを行うことで予後因子を同定してきた。今回我々はこれまでAMLを含む悪性疾患で報告のある遺伝子や、治療薬が開発されている遺伝子について網羅した343遺伝子パネルを用いて、次世代シーケンサーを使用したtargeted deep sequencingを立案した。解析の結果抽出された遺伝子変異について臨床データとの比較検討を行い、特定された遺伝子変異の変異頻度、臨床的特徴、予後との関係、その他の遺伝学的背景との相関関係を調べ、それらの遺伝子変異の重要性を決定する。

Outline of Final Research Achievements

Currently, the long-term survival rate of pediatric acute myeloid leukemia (AML) improved 60-70%. Recently, clinical sequences are used to determine the therapeutic methods of many cancers. Pediatric AML is also needed more genome information to perform clinical sequences for precision medicine. Here, we performed targeted sequencing using a 343-gene custom panel and next-generation sequencer in pediatric patients with de novo AML. As a result, we found recurrent gene mutations such as PTPN11, TET2, and TP53 which might be associated with outcome of AML. And we reported these results in the 60th and 61st American Society of Hematology Annual Meeting. Now, we have performed further analyses to determine the relations between genetic mutations and clinical features and prepared for submitting these significant results.

Academic Significance and Societal Importance of the Research Achievements

近年がん領域で米国を中心にクリニカルシーケンスが実臨床に用いられるようになり、国内においても普及し始めている。クリニカルシーケンスは解析で得られた網羅的な患者ゲノム情報を基に治療方針や治療薬の選択が行われ、プレシジョンメディスンとほぼ同義である。治療方針の決定は過去の学術論文や構築されたデータベースを基盤としている。小児急性骨髄性白血病(AML)においても予後因子となりうる遺伝子変異の同定は急務である。本研究は小児AMLの網羅的遺伝子解析を行い、予後に関与しうる複数の遺伝子を同定した今後のプレシジョンメディスンへの基礎となりうる研究であり、将来の小児AML予後改善へつながる可能性を持っている。

Research Products

• [Journal Article] Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup. (2020)
  • Author(s): Hara Y, Shiba N, Yamato G, Ohki K, Tabuchi K, Sotomatsu M, Tomizawa D, Kinoshita A, Arakawa H, Saito AM, Kiyokawa N, Tawa A, Horibe K, Taga T, Adachi S, Taki T, Hayashi Y
  • Journal Title: Br J Haematol Volume: 188 Issue: 4 Pages: 528-539
  • DOI: 10.1111/bjh.16203
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transcriptome analysis offers a comprehensive illustration of the genetic background of pediatric acute myeloid leukemia (2019)
  • Author(s): Shiba N, Yoshida K, Hara Y, Yamato G, Shiraishi Y, Matsuo H, Okuno Y, Chiba K, Tanaka H, Kaburagi T, Takeuchi M, Ohki K, Sanada M, Okubo J, Tomizawa D, Taki T, Shimada A, Sotomatsu M, Horibe K, Taga T, Adachi S, Tawa A, Miyano S, Ogawa S, Hayashi Y
  • Journal Title: Blood Adv Volume: 3 Issue: 20 Pages: 3157-3169
  • DOI: 10.1182/bloodadvances.2019000404
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Predictive factors of the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome: the JCCG study JPLSG TAM-10 (2019)
  • Author(s): Yamato G, Muramatsu H, Watanabe T, Deguchi T, Iwamoto S, Hasegawa D, Terui K, Ueda T, Yokosuka T, Toki T, Tanaka S, Yanagisawa R, Koh K, Saito A, Horibe K, Hayashi Y, Adachi S, Mizutani S, Taga T, Ito E, Watanabe K.
  • Organizer: 61st American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Significant features of DNA methylation at bivalent promotor and repressed polycomb regions in pediatric AML -the JCCG study, JPLSG AML-05- (2019)
  • Author(s): Yamato G, Kawai T, Shiba N, Hara Y, Ohki K, Kaburagi T, Yoshida K, Shiraishi Y, Miyano S, Kiyokawa N, Tomizawa D, Shimada A, Sotomatsu M, Arakawa H, Adachi S, Taga T, Horibe K, Ogawa S, Hata K, Hayashi Y.
  • Organizer: 61st American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] 小児急性骨髄性白血病における網羅的メチル化解析 -The JCCG-JPLSG AML-05 study- (2019)
  • Author(s): 大和玄季，河合智子, 柴 徳生, 原 勇介, 大木 健太郎, 鏑木多映子, 吉田 健一, 白石友一, 宮野悟, 清河信敬, 富澤 大輔 , 嶋田明, 外松 学, 荒川 浩一 , 足立 壮一, 多賀 崇 , 堀部 敬三, 小川 誠司, 秦健一郎, 林 泰秀
  • Organizer: 第81回日本血液学会
• [Presentation] 一過性骨髄異常増殖症患者における白血病発症関連因子について：JCCG JPLSG TAM-10 study- (2019)
  • Author(s): 大和玄季、村松秀城、渡邊智之、出口隆生、岩本彰太郎、長谷川大輔、照井君典、植田高弘、横須賀とも子、田中司朗、柳沢龍、康勝好、齋藤明子、堀部敬三、林 泰秀、足立壮一、水谷修紀、多賀 崇、伊藤悦朗、渡邉健一郎
  • Organizer: 第61回日本小児血液・がん学会
• [Presentation] Recurrent gene mutations in pediatric patients with AML by targeted sequencing -the JCCG study, JPLSG AML-05- (2019)
  • Author(s): Kaburagi T, Yamato G, Shiba N, Yoshida K, Hara Y, Shiraishi Y, Ohki K, Sotomatsu M, Arakawa H, Matsuo H, Shimada A, Taki T, Kiyokawa N, Tomizawa D, Horibe K, Miyano S, Taga T, Adachi S, Ogawa S, Hayashi Y
  • Organizer: 61st American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Comprehensive Analysis of 343 Genes using Targeted Sequencing Panel by Next-Generation Sequencer In 77 Pediatric AML Patients with Normal and Complex Karyotypes: JCCG Study, JPLSG AML-05 (2018)
  • Author(s): Taeko Kaburagi, Genki Yamato, et al.
  • Organizer: 60th Annual Meeting of the American Society of Hematology
  • Int'l Joint Research