Investigations of pathophysiology of malignant tumors in animals using next generation sequencing

• Project/Area Number: 17H03921
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Veterinary medical science
• Research Institution: The University of Tokyo
• Principal Investigator: Tsujimoto Hajime 東京大学, 大学院農学生命科学研究科(農学部), 教授 (60163804)
• Co-Investigator(Kenkyū-buntansha): 渡邊 学 東京大学, 大学院新領域創成科学研究科, 特任教授 (70376606) ; 富安 博隆 東京大学, 大学院農学生命科学研究科(農学部), 助教 (70776111)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000); Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: 分子病理学 / RNAシーケンシング / エキソーム解析 / 腫瘍 / バイオインフォマティクス / エキソーム解析s

Outline of Final Research Achievements

In veterinary medicine, diagnosis and treatment for malignant tumors have been determined based on histopathological examinations. In this study, we conducted molecular biological examinations that comprehensively analyzed gene expression profiles and genomic abnormalities by next-generation sequencing, and novel pathophysiology of canine malignant tumors were revealed.
In particular, we performed vigorous analysis for canine histiocytic sarcoma, and it was revealed that there were various molecular biological abnormalities in individual cases, but specific signal pathways were commonly dysregulatd in tumor cells. In addition, it was suggested that novel effective treatments could be developed by targeting the responsible molecule in these signal pathways.

Academic Significance and Societal Importance of the Research Achievements

近年動物においても悪性腫瘍が主な死因となっており、その治療成績の向上は急務となっている。本研究は、これまで獣医学領域において主に病理組織学的探索を基に診断や治療方針を決定してきた悪性腫瘍に関して、遺伝子発現プロファイルやゲノム異常といった分子生物学的探索を取り入れることで、より適切な診断や治療法選択を可能とすることを目指してきた。
本研究から得られた成果によって犬の悪性腫瘍の新たな病態が明らかとなりまた新規治療法の可能性も見出された。この成果は獣医学領域のみならず人医学領域における臨床腫瘍学の発展にも貢献するものと考えている。

Research Products

• [Int'l Joint Research] University of California, Davis(米国)
• [Journal Article] Comparison of the efficacy of cyclosporine and leflunomide in treating inflammatory colorectal polyps in miniature dachshunds (2020)
  • Author(s): Tani A、Seno T、Yokoyama N、Nakagawa T、Tomiyasu H、Goto-Koshino Y、Tsujimoto H、Ohno K
  • Journal Title: Journal of Veterinary Medical Science Volume: 82 Issue: 4 Pages: 437-440
  • DOI: 10.1292/jvms.19-0560
  • NAID: 130007829876
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Effect of a two-base insertion mutation of the TP53 gene on expression of p53 protein in canine histiocytic sarcoma cells. (2019)
  • Author(s): Asada H, Toiyasu H, Goto-Koshino Y, Ohno K, Tsujimoto H
  • Journal Title: Am J Vet Res Volume: 80 Issue: 7 Pages: 680-688
  • DOI: 10.2460/ajvr.80.7.680
  • Peer Reviewed
• [Journal Article] Development of canine X-chromosome inactivation pattern analysis for the detection of cell clonality by incorporating the examination of the SLIT and NTRK-like family member 4 (SLITRK4) gene. (2019)
  • Author(s): Tomita A, Mochizuki H, Tsuboi M, Ogura I, Igarashi H, Goto-Koshino Y, Takahashi M, Ohmi A, Tomiyasu H, Ohno K, Nakagawa T, Uchida K, Nishimura R, Tsujimoto H
  • Journal Title: Res Vet Sci Volume: 125 Pages: 170-175
  • DOI: 10.1016/j.rvsc.2019.06.004
  • Peer Reviewed
• [Journal Article] Blastic natural killer cell lymphoma/leukaemia in a cat (2019)
  • Author(s): Hirabayashi M、Chambers JK、Sugawara M、Ohmi A、Tsujimoto H、Nakayama H、Uchida K
  • Journal Title: Journal of Feline Medicine and Surgery Open Reports Volume: 5 Issue: 2 Pages: 205511691986308-205511691986308
  • DOI: 10.1177/2055116919863080
  • Peer Reviewed / Open Access
• [Journal Article] Retrospective study of canine cutaneous tumors in Japan, 2008?2017 (2019)
  • Author(s): KOK Mun Keong、CHAMBERS James K.、TSUBOI Masaya、NISHIMURA Ryohei、TSUJIMOTO Hajime、UCHIDA Kazuyuki、NAKAYAMA Hiroyuki
  • Journal Title: Journal of Veterinary Medical Science Volume: 81 Issue: 8 Pages: 1133-1143
  • DOI: 10.1292/jvms.19-0248
  • NAID: 130007695246
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive analysis of miRNA and protein profiles within exosomes derived from canine lymphoid tumour cell lines. (2019)
  • Author(s): Asada H, Yomiyasu H, Uchikai T, Ishihara G, Goto-Koshino Y, Ohno K, Tsujimoto H
  • Journal Title: PLoS One Volume: 14 Issue: 4 Pages: e0208567-e0208567
  • DOI: 10.1371/journal.pone.0208567
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of cell line and in vivo mouse model of canine Langerhans cell histiocytosis (2019)
  • Author(s): Son Nguyen V.、Uchida Kazuyuki、Thongtharb Atigan、Chambers James K.、Kishimoto Takuya E.、Tomiyasu Hirotaka、Ohmi Aki、Tsujimoto Hajime、Nakayama Hiroyuki
  • Journal Title: Veterinary and Comparative Oncology Volume: - Issue: 3 Pages: 345-353
  • DOI: 10.1111/vco.12476
  • Peer Reviewed
• [Journal Article] Clinical significance of the two-base insertion mutation in the TP53 gene in canine histiocytic sarcoma. (2019)
  • Author(s): Asada H, Tomiyasu H, Okada K, Chambers JK, Goto-Koshino Y, Uchida K, Kagawa Y, Ohno K, Tsujimoto H.
  • Journal Title: Res Vet Sci Volume: 124 Pages: 57-60
  • DOI: 10.1016/j.rvsc.2019.03.003
  • Peer Reviewed
• [Journal Article] The intratumor heterogeneity of <i>TP53</i> gene mutations in canine histiocytic sarcoma (2019)
  • Author(s): Asada H, Ichii O, Tomiyasu H, Uchida K, Chambers JK, Goto-Koshino Y, Ohno K, Kon Y, Tsujimoto H.
  • Journal Title: Journal of Veterinary Medical Science Volume: 81 Issue: 3 Pages: 353-356
  • DOI: 10.1292/jvms.18-0419
  • NAID: 130007612993
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistochemical Profiling of Canine Intestinal T-Cell Lymphomas. (2019)
  • Author(s): Matsumoto I, Nakashima K, Goto-Koshino Y, Chambers JK, Tsujimoto H, Nakayama H, Uchida K.
  • Journal Title: Vet Pathol Volume: 56 Issue: 1 Pages: 50-60
  • DOI: 10.1177/0300985818800015
  • Peer Reviewed
• [Journal Article] Clinical and clinicopathological characteristics of acute lymphoblastic leukaemia in six cats. (2018)
  • Author(s): Tomiyasu H, Doi A, Chambers JK, Goto-Koshino Y, Ohmi A, Ohno K, Tsujimoto H.
  • Journal Title: J Small Anim Pract Volume: 59 Issue: 12 Pages: 742-746
  • DOI: 10.1111/jsap.12917
  • Peer Reviewed
• [Journal Article] Prognostic value of CD44 variant isoform expression in dogs with multicentric high-grade B-cell lymphoma. (2018)
  • Author(s): Motegi T, Tomiyasu H, Goto-Koshino Y, Takahashi M, Hiyoshi-Kanemoto S, Fujino Y, Ohno K, Tsuimoto H.
  • Journal Title: Am J Vet Res Volume: 79 Issue: 9 Pages: 961-969
  • DOI: 10.2460/ajvr.79.9.961
  • Peer Reviewed
• [Journal Article] Prognostic significance of hypermethylation of death-associated protein kinase (DAPK) gene CpG island in dogs with high-grade B-cell lymphoma (2018)
  • Author(s): Sato, M., Mochizuki, H., Goto-Koshino, Y., Fujiwara-Igarashi, A., Takahashi, M., Ohno, K. and Tsujimoto, H.
  • Journal Title: Veterinary and Comparative Oncology Volume: 印刷中 Issue: 3 Pages: 409-415
  • DOI: 10.1111/vco.12395
  • Peer Reviewed
• [Journal Article] Pathological features of intestinal T‐cell lymphoma in Shiba dogs in Japan (2018)
  • Author(s): Matsumoto I., Uchida, K., Nakashima, K., Goto-Koshino, Y., Chambers, J., Tsujimoto, H. and Nakayama, H.
  • Journal Title: Veterinary and Comparative Oncology Volume: 印刷中 Issue: 4 Pages: 417-423
  • DOI: 10.1111/vco.12396
  • Peer Reviewed
• [Journal Article] Detection of monoclonality in intestinal lymphoma with polymerase chain reaction for antigen receptor gene rearrangement analysis to differentiate from enteritis in dogs (2017)
  • Author(s): Ohmura, S., Leipig, M., Schopper, I., Hergt, F., Weber, K., Rutgen, B.C., Tsujimoto, H., Hermanns, W. and Hirschberger, J.
  • Journal Title: Veterinary and Comparative Oncology Volume: 15 Issue: 1 Pages: 194-207
  • DOI: 10.1111/vco.12151
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Melting curve analysis in canine lymphoma by calculating maximum fluorescence decrease (2017)
  • Author(s): Schopper, I., Ohmura, S., Rutgen, B., Tsujimoto, H., Weber, K. and Hirschberger, J.
  • Journal Title: Veterinary and Comparative Oncology Volume: 15 Issue: 2 Pages: 563-575
  • DOI: 10.1111/vco.12200
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of a novel canine T-cell line established from a dog with cutaneous T-cell lymphoma (2017)
  • Author(s): Hara, K., Iio, A., Asahina, R., Takahashi, M., Mori, T., Nishida, H., Kamishina, H., Sakai, H., Kitoh, K., Mizuno, T., Tsujimoto, H. and Maeda, S.
  • Journal Title: Journal of Dermatological Science Volume: 88 Issue: 2 Pages: 254-256
  • DOI: 10.1016/j.jdermsci.2017.06.001
  • Peer Reviewed
• [Journal Article] Significance of clonal rearrangements of lymphocyte antigen receptor genes on the prognosis of chronic enteropathy in 22 Shiba dogs (2017)
  • Author(s): Ohmi, A., Ohno, K., Uchida, K., Goto-Koshino, Y., Tomiyasu, H., Kanemoto, H., Fikushima, K. and Tsujimoto, H.
  • Journal Title: Journal of Veterinary Medical Science Volume: 79 Issue: 9 Pages: 1578-1584
  • DOI: 10.1292/jvms.16-0626
  • NAID: 130006106445
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive analysis of gene expression profiles reveals novel candidates of chemotherapy resistant factors in canine lymphoma (2017)
  • Author(s): Suenaga, M., Tomiyasu, H., Watanabe, M., Ogawa, K., Motegi, T., Goto-Koshino, Y., Ohno, K., Sugano, S., Skorupski, K.A. and Tsujimoto, H.
  • Journal Title: The Veterinary Journal Volume: 228 Pages: 18-21
  • DOI: 10.1016/j.tvjl.2017.10.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IgA Antibodies Against Gliadin and Tissue Transglutaminase in Dogs With Chronic Enteritis and Intestinal T-Cell Lymphoma (2017)
  • Author(s): Matsumoto, I., Uchida, K., Nakashima, K., Hiyoshi, S., Chambers, J.K., Tsujimoto, H. and Nakayama, H.
  • Journal Title: Veterinary Pathology Volume: 55 Issue: 1 Pages: 98-107
  • DOI: 10.1177/0300985817690212
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A 2-base insertion in exon 5 is a common mutation of the <i>TP53</i> gene in dogs with histiocytic sarcoma (2017)
  • Author(s): Asada, H., Tsuboi, M., Chambers, J.K., Uchida K., Tomiyasu, H., Goto-Koshino, Y., Ohno, K. and Tsujimoto, H.
  • Journal Title: Journal of Veterinary Medical Science Volume: 79 Issue: 10 Pages: 1721-1726
  • DOI: 10.1292/jvms.17-0197
  • NAID: 130006176479
  • ISSN: 0916-7250, 1347-7439
  • Peer Reviewed / Open Access
• [Presentation] リバーロキサバンの投与を行った血栓症の犬23 例の回顧的検討 (2019)
  • Author(s): 福岡玲，大参亜紀，山本貴恵，藤原玲奈，富安博隆，大野耕一，辻本 元
  • Organizer: 第16回日本獣医内科学アカデミー学術大会
• [Presentation] 犬の全血輸血における副反応発生頻度およびその危険因子に関する検討 (2019)
  • Author(s): 谷章禎，富安博隆，大参亜紀，大野耕一，辻本元
  • Organizer: 第16回日本獣医内科学アカデミー学術大会
• [Presentation] Demonstration of clonal hematopoiesis in miniature dachshunds affected with nonregenerative anemia (2019)
  • Author(s): Tani A、Tomiyasu H、Ohmi A、Ohno K、Tsujimoto H
  • Organizer: Asian Meeting of Animal Medicine Specialties 2019
  • Int'l Joint Research
• [Presentation] Application of a gene expression scoring system to predict chemotherapy sensitivity in canine lymphoma (2019)
  • Author(s): Saegusa Y、Tani A、Ogawa K、Takeuchi Y、Tomiyasu H、Ohno K、Tsujimoto H
  • Organizer: Asian Meeting of Animal Medicine Specialties 2019
  • Int'l Joint Research
• [Presentation] Genetic mutations detected in Miniature Dachshunds diagnosed with myelodysplastic syndrome (MDS) in Japan (2019)
  • Author(s): Tani A、Tomiyasu H、Uchikai T、Matsumoto Y、Ishihara G、Goto-Koshino Y、Ohno K、Tsujimoto H
  • Organizer: American College of Veterinary Internal Medicine Forum 2019
  • Int'l Joint Research
• [Presentation] 犬のランゲルハンス細胞組織球症3 症例における臨床的・病理学的特徴の検討 (2019)
  • Author(s): 横井史花，大参亜紀，チェンバーズ ジェームズ，坪井誠也，内田和幸，富安博隆，大野耕一，辻本 元
  • Organizer: 第15回日本獣医内科学アカデミー学術大会
• [Presentation] 犬の大細胞性胃腸管型リンパ腫に対するL- アスパラギナーゼ連続投与の有効性 (2019)
  • Author(s): 小島麻里，中川泰輔，横山 望，大参亜紀，富安博隆，大野耕一，辻本 元
  • Organizer: 第15回日本獣医内科学アカデミー学術大会
• [Presentation] T-cell-rich large B-cell lymphomaの猫の2 例 (2019)
  • Author(s): 菅原芽伊，大参亜紀，佐藤 茜，佐野頼典，坪井誠也，チェンバーズ・ジェームズ， 内田和幸，富安博隆，後藤（越野）裕子，大野耕一，辻本 元
  • Organizer: 第15回日本獣医内科学アカデミー学術大会
• [Presentation] 犬の大細胞性消化器型リンパ腫に関連した消化管穿孔に関する回顧的研究 (2019)
  • Author(s): 杉浦 叶，中川泰輔，横山 望，大参亜紀，富安博隆，大野耕一，辻本 元
  • Organizer: 第15回日本獣医内科学アカデミー学術大会
• [Presentation] Comprehensive analysis of gene mutation in canine histiocytic sarcoma by whole exome sequencing (2018)
  • Author(s): Hajime Asada, Takao Uchikai, Hirotaka Tomiyasu, Genki Ishihara, Yuko Goto-Koshino, Koichi Ohno, Hajime Tsujimoto
  • Organizer: American College of Veterinary Internal Medicine Forum
  • Int'l Joint Research
• [Presentation] イヌDLBCLにおけるゲノムワイドDNAメチル化パターンと予後との関連 (2018)
  • Author(s): 久本真也、山崎淳平、茂木朋貴、富安博隆、後藤（越野）裕子、辻本元、稲葉睦
  • Organizer: 第14回日本獣医内科学アカデミー学術大会
• [Presentation] ジャックラッセルテリアにおける消化管腺癌の臨床的特徴と予後 (2018)
  • Author(s): 大参亜紀、大野耕一、横山望、中川泰輔、富安博隆、チェンバーズ・ジェームズ、内田和幸、辻本元
  • Organizer: 第14回日本獣医内科学アカデミー学術大会
• [Presentation] 消化管T細胞性リンパ腫の犬種特異性に関する検討 (2017)
  • Author(s): 松本功、内田和幸、中島亘、後藤裕子、チェンバーズ・ジェームズ、大参亜紀、福島建次郎、大野耕一、辻本元、中山裕之
  • Organizer: 第160回日本獣医学会学術集会
• [Presentation] 次世代型シークエンサーを用いたイヌ腫瘍症例の臨床がんゲノム解析 (2017)
  • Author(s): 渡邊学、田坂徹悟、坪井誠也、田中由衣子、湯祥彦、藤原亜紀、長谷川大輔、遠藤能史、中川貴之、内田和幸、中山裕之、辻本元、西村亮平、菅野純夫
  • Organizer: 第160回日本獣医学会学術集会
• [Presentation] A 2-Base Insertion Mutation of TP53 Gene and its Intratumor Heterogeneity in Canine Histiocytic Sarcoma (2017)
  • Author(s): Asada Hajime, Ichii Osamu, Tomiyasu Hirotaka, Tsuboi Masaya, Uchida Kazuyuki, Goto-Koshino Yuko, Ohno Koichi, Kon Yasuhiro, Tsujimoto Hajime
  • Organizer: Veterinary Cancer Society Annual Conference 2017
  • Int'l Joint Research
• [Presentation] A Gene Expression Scoring System to Predict Chemotherapy Resistance Using Novel Drug Resistance Factors in Canine Lymphoma (2017)
  • Author(s): Ogawa Kotoko, Tomiyasu Hirotaka, Suenaga Miyu, Watanabe Manabu, Sugano Sumio, Motegi Tomoki, Takeuchi Yoshinori, Omi Aki, Goto-Koshino Yuko, Ohno Koichi, Skorupski Katherine, Tsujimoto Hajime
  • Organizer: Veterinary Cancer Society Annual Conference 2017
  • Int'l Joint Research
• [Remarks] 東京大学 獣医内科学教室 血液・腫瘍性疾患 研究チーム
  • URL: https://www.vetinternmed-oncology.com