Integrated analysis of various chromosomal and genomic structures of tumors and the molecular mechanism of abnormal transcript formation

• Project/Area Number: 18K08335
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyorin University
• Principal Investigator: TAKI TOMOHIKO 杏林大学, 保健学部, 教授 (50322053)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: がん / ゲノム / 染色体 / 融合遺伝子 / キメラ遺伝子 / 構造異常 / エクソン / イントロン / 転写産物

Outline of Final Research Achievements

We attempted to predict the chromosomal structural abnormalities involved in its formation, based on the fusion gene product information extracted from the transcriptome sequencing data of 100 hematologic tumor cell lines. Of particular interest was the fact that one gene forms a fusion gene with multiple genes in a single cell line, and the combination of such fusion genes was defined as "promiscuous fusion". There were 74 types of promiscuous fusion in 38 cell lines. The formation mode of promiscuous fusion can be divided into those that can be explained by a simple one structural change, such as 3-way translocation or deletion insertion, and those that cannot be formed by one structural change. It was considered to be useful as a new method of genomic structure analysis.

Academic Significance and Societal Importance of the Research Achievements

次世代シーケンサーによるシーケンスのコストが下がり、膨大なゲノム情報が容易に手に入る時代になってきた。その解析のためのインフォマティクスも進歩している。しかし、現時点ではまだ、見つかったゲノム情報の一部しか利用されていない。ゲノム情報がたった4種類の塩基配列情報からなるのに対して、ゲノム構造は23対の染色体によって形成される非常に複雑なものであることも起因している。そのため、検出された異常の多くがその意味を正確に理解されていない。急速に進みつつあるゲノム医療においても、意義が明確でないゲノム異常を正確に理解することは、疾患の正確な診断やそれに基づく治療法の選択にとって重要な課題である。

Research Products

• [Journal Article] Nationwide study of pediatric B-cell precursor acute lymphoblastic leukemia with chromosome 8q24/MYC rearrangement in Japan. (2020)
  • Author(s): Sakaguchi K, Imamura T, Ishimaru S, Imai C, Shimonodan H, Fujita N, Okada K, Taketani T, Kanai R, Tauchi H, Kato M, Kojima Y, Watanabe A, Deguchi T, Hashii Y, Kiyokawa N, Taki T, Saito AM, Horibe K, Manabe A, Sato A, Koh K.
  • Journal Title: Pediatr Blood Cancer Volume: 67 Issue: 7
  • DOI: 10.1002/pbc.28341
  • NAID: 120007161473
  • Peer Reviewed
• [Journal Article] A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial (2020)
  • Author(s): Tomizawa D、Miyamura T、Imamura T、Watanabe T、Saito A、Ogawa A、Takahashi Y、Hirayama M、Taki T、Deguchi T、Hori T、Sanada M、Ohmori S、Haba M、Iguchi A、Arakawa Y、Koga Y、Manabe A、Horibe K、Ishii E、Koh K
  • Journal Title: Blood Volume: 136 Issue: 16 Pages: 1813-1823
  • DOI: 10.1182/blood.2019004741
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A pediatric case of secondary T-cell acute lymphoblastic leukemia with KMT2A-MAML2 developing after hepatoblastoma treatment (2020)
  • Author(s): Takahashi Y, Terui K, Chinen Y, Tandai S, Kudo K, Sasaki S, Tono C, Taki T, Ito E
  • Journal Title: Pediatr Blood Cancer Volume: 67 Issue: 1
  • DOI: 10.1002/pbc.28033
  • Peer Reviewed
• [Journal Article] Recurrent intragenic exon rearrangements of SOBP and AUTS2 in non-Hodgkin B-cell lymphoma (2020)
  • Author(s): Matsumoto Y, Chinen Y, Shimura Y, Nagoshi H, Sasaki N, Muramatsu A, Kuriyama K, Ohshiro M, Hirakawa Y, Iwai T, Uchiyama H, Taki T, Horiike S, Kuroda J, Taniwaki M
  • Journal Title: Int J Hematol Volume: 111 Issue: 1 Pages: 75-83
  • DOI: 10.1007/s12185-019-02766-z
  • Peer Reviewed
• [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] Three Consecutive Cases of Familial Hemophagocytic Lymphohistiocytosis, Including a Case Due to Maternal Uniparental Disomy. (2019)
  • Author(s): 2.Sato H, Kawasaki N, Kawasaki M, Abiko Y, Meguro T, Takahashi N, Izumino H, Kanno M, Numakura C, Sasaki A, Imamura T, Taki T, Mitsui T.
  • Journal Title: J Pediatr Hematol Oncol. Volume: - Issue: 8 Pages: e819-e821
  • DOI: 10.1097/mph.0000000000001681
  • Peer Reviewed
• [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
• [Journal Article] Nationwide survey of pediatric hypodiploid acute lymphoblastic leukemia in Japan (2019)
  • Author(s): Ishimaru Sae、Okamoto Yasuhiro、Imai Chihaya、Sakaguchi Hirotoshi、Taki Tomohiko、Hasegawa Daisuke、Cho Yuko、Kakuda Harumi、Sano Hideki、Manabe Atsushi、Imamura Toshihiko、Kato Motohiro、Arakawa Yuki、Shimonodan Hidemi、Sato Atsushi、Suenobu Souichi、et al.
  • Journal Title: Pediatrics International Volume: 61 Issue: 11 Pages: 1103-1108
  • DOI: 10.1111/ped.14006
  • Peer Reviewed / Open Access
• [Journal Article] Nationwide survey of therapy-related leukemia in childhood in Japan (2018)
  • Author(s): Imamura T, Taga T, Takagi M, Kawasaki H, Koh K, Taki T, Adachi S, Manabe A, Ishida Y; Leukemia/Lymphoma Committee; Japanese Society of Pediatric Hematology Oncology (JSPHO)
  • Journal Title: Int J Hematol Volume: 108 Issue: 1 Pages: 91-97
  • DOI: 10.1007/s12185-018-2439-x
  • Peer Reviewed
• [Journal Article] Clinical characteristics of pediatric patients with myeloid sarcoma without bone marrow involvement in Japan (2018)
  • Author(s): Taga T, Imamura T, Nakashima K, Maeda N, Watanabe A, Miyajima Y, Sakaguchi S, Sano H, Hasegawa D, Kawasaki H, Adachi S, Takagi M, Koh K, Manabe A, Taki T, Ishida Y
  • Journal Title: Int J Hematol Volume: 108 Issue: 4 Pages: 438-442
  • DOI: 10.1007/s12185-018-2492-5
  • Peer Reviewed
• [Presentation] Analysis of chromosomal and genomic structure based on the information of fusion genes revealed by RNA-sequencing (2020)
  • Author(s): Tetsuko Kobayashi, Tomohiko Taki
  • Organizer: 第62回日本小児血液・がん学会学術集会
• [Presentation] Recurrent gene mutations in pediatric AML by targeted sequencing using a 343-gene custom panel (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, Adachi S, Taga T, Ogawa S, Hayashi Y
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] TP53 遺伝子異常を伴う小児急性骨髄性白血病の臨床像と分子生物学異常の解析 (2019)
  • Author(s): Hara Y, Taki T, Yamato G, Yoshida K, Shiba N, Kaburagi T, Shiraishi Y, Ohki K, Kawamura M, Sotomatsu M, Arakawa H, Matsuo H, Shimada A, Toki T, Kiyokawa N, Tomizawa D, Taga T, Ito E, Horibe K, Miyano S, Ogawa S, Adach S, Hayashi Y
  • Organizer: 第61回日本小児血液・がん学会学術集会
• [Presentation] 乳児急性リンパ性白血病に対する層別化治療:日本小児白血病リンパ腫研究グループ MLL-10 臨床試験の報告 (2019)
  • Author(s): Tomizawa D, Miyamura T, Imamura T, Watanabe T, Saito A, Ogawa A, Takahashi Y, Hirayama M, Arakawa Y, Taki T, Deguchi T, Hori T, Omori S, Haba M, Iguchi A, Koga Y, Manabe A, Horibe K, Ishii E, Koh K
  • Organizer: 第61回日本小児血液・がん学会学術集会
• [Presentation] 小児急性骨髄性白血病患者における KMT2C 変異と PHF6 変異の臨床的意義について (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, Adachi S, Taga T, Ogawa S, Hayashi Y
  • Organizer: 第61回日本小児血液・がん学会学術集会
• [Presentation] Novel fusion gene PVT1-ELK2AP in a B-cell lymphoma cell line with MYC-IGH gene rearrangement (2018)
  • Author(s): 松本洋典, 滝智彦, 知念良顕, 佐々木奈々, 吉田美穂子, 堤康彦, 名越久朗, 志村和穂, 兼子裕人, 堀池重夫, 黒田純也, 谷脇雅史
  • Organizer: 第80回日本血液学会学術集会