Analysis of chromosomal structural variations associated with increased expression of tumor growth factor-alpha in triple-negative breast cancer

• Project/Area Number: 18K07320
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Kawazu Masahito 国立研究開発法人国立がん研究センター, 研究所, ユニット長 (20401078)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 乳がん / ロングリードシーケンサー / 全長RNAシーケンス / 染色体構造異常 / トリプルネガティブ乳がん / ゲノム解析 / ゲノム構造異常

Outline of Final Research Achievements

To elucidate the pathogenesis of triple-negative breast cancer （TNBC）, we performed comprehensive full-length RNA sequencing by long read sequencing using clinical specimens from 14 TNBCs and 8 estrogen receptor-positive breast cancers. We revealed a landscape of the transcriptome in breast cancer and identified subtype-specific isoforms in several genes. In particular, we found that a novel variant of TNS3, a gene involved in cytoskeletal regulation, is expressed specifically in TNBC and has implication in its pathogenesis. In addition, we discovered a novel mechanism of immune evasion in which the expression of the endogenous retroviral gene ERVFRD-1 is de-repressed as a consequence of chromosomal structural abnormalities.

Academic Significance and Societal Importance of the Research Achievements

ここ数年のロングリードシーケンサー技術の進歩により、がんゲノム解析研究へのロングリードシーケンサーの応用の期待が高まっている。しかしながら、そのデータ解析手法は発展途上であり、詳細なデータ解析が十分に行われていないのが現状である。本研究においては網羅的全長RNAシーケンスの解析パイプラインを開発し、それによりこれまで知られていなかったトリプルネガティブ乳がんの病態を明らかにした。本研究で示した解析の枠組みを応用することで、ロングリードシーケンサーによるがんゲノム研究が推進されることが期待される。

Research Products

• [Journal Article] The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies (2020)
  • Author(s): Kumagai S,Togashi Y,Kamada T,Sugiyama E,Nishinakamura H,Takeuchi Y,Vitaly K,Itahashi K,Maeda Y,Matsui S,Shibahara T,Yamashita Y,Irie T,Tsuge A,Fukuoka S,Kawazoe A,Udagawa H,Kirita K,Aokage K,Ishii G,Kuwata T,Nakama K,Kawazu M,Ueno T,Yamazaki N,Goto K,Tsuboi M,Mano H,Doi T,Shitara K,Nishikawa H
  • Journal Title: Nature Immunology Volume: 21 Issue: 11 Pages: 1346-1358
  • DOI: 10.1038/s41590-020-0769-3
  • Peer Reviewed / Open Access
• [Journal Article] A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma (2020)
  • Author(s): Tateishi Kensuke、Miyake Yohei、Kawazu Masahito、Sasaki Nobuyoshi、Nakamura Taishi、Sasame Jo、Yoshii Yukie、Ueno Toshihide、Miyake Akio、Matsushita Yuko、Shiba Norio、Udaka Naoko、Ohki Kentaro、Fink Alexandria L.、Tummala Shilpa S.、Natsumeda Manabu、Miller Julie J.、Fujii Yukihiko、et al
  • Journal Title: Cancer Research Volume: 80 Issue: 23 Pages: 5330-5343
  • DOI: 10.1158/0008-5472.can-20-2425
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Multicenter Phase I/II Trial of Napabucasin and Pembrolizumab in Patients with Metastatic Colorectal Cancer (EPOC1503/SCOOP Trial) (2020)
  • Author(s): Kawazoe Akihito、Kuboki Yasutoshi、Shinozaki Eiji、Hara Hiroki、Nishina Tomohiro、Komatsu Yoshito、Yuki Satoshi、Wakabayashi Masashi、Nomura Shogo、Sato Akihiro、Kuwata Takeshi、Kawazu Masahito、Mano Hiroyuki、Togashi Yosuke、Nishikawa Hiroyoshi、Yoshino Takayuki
  • Journal Title: Clinical Cancer Research Volume: 26 Issue: 22 Pages: 5887-5894
  • DOI: 10.1158/1078-0432.ccr-20-1803
  • Peer Reviewed / Open Access
• [Journal Article] An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells (2020)
  • Author(s): Shogo Kumagai, Yosuke Togashi, Chika Sakai, Akihito Kawazoe, Masahito Kawazu, Toshihide Ueno, Eiichi Sato, Takeshi Kuwata, Takahiro Kinoshita, Masami Yamamoto, Sachiyo Nomura, Tetsuya Tsukamoto, Hiroyuki Mano, Kohei Shitara, Hiroyoshi Nishikawa
  • Journal Title: Immunity Volume: 14 Issue: 1 Pages: 187-203
  • DOI: 10.1016/j.immuni.2020.06.016
  • NAID: 120006952281
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] KRAS mutations in uterine endometrium are associated with gravidity and parity. (2020)
  • Author(s): Inoue, S., Yoshida, E., Fukui, Y., Ueno, T., Kawazu, M., Takeyama, R., Ikemura, M., Osuga, Y., Terao, Y., Hirota, Y., Mano, H.
  • Journal Title: Cell Death Disease Volume: 11 Issue: 5 Pages: 347-347
  • DOI: 10.1038/s41419-020-2559-0
  • Peer Reviewed / Open Access
• [Journal Article] A germline HLTF mutation in familial MDS induces DNA damage accumulation through impaired PCNA polyubiquitination (2019)
  • Author(s): Takaoka Kensuke、Kawazu Masahito、Koya Junji、Yoshimi Akihide、Masamoto Yosuke、Maki Hiroaki、Toya Takashi、Kobayashi Takashi、Nannya Yasuhito、Arai Shunya、Ueno Toshihide、Ueno Hironori、Suzuki Kenshi、Harada Hironori、Manabe Atsushi、Hayashi Yasuhide、Mano Hiroyuki、Kurokawa Mineo
  • Journal Title: Leukemia Volume: 印刷中 Issue: 7 Pages: 1773-1782
  • DOI: 10.1038/s41375-019-0385-0
  • Peer Reviewed
• [Journal Article] Differential regulation of CpG island methylation within divergent and unidirectional promoters in colorectal cancer (2019)
  • Author(s): Namba Shinichi、Sato Kazuhito、Kojima Shinya、Ueno Toshihide、Yamamoto Yoko、Tanaka Yosuke、Inoue Satoshi、Nagae Genta、Iinuma Hisae、Hazama Shoichi、Ishihara Soichiro、Aburatani Hiroyuki、Mano Hiroyuki、Kawazu Masahito
  • Journal Title: Cancer Science Volume: 110 Issue: 3 Pages: 1096-1104
  • DOI: 10.1111/cas.13937
  • Peer Reviewed / Open Access
• [Journal Article] Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations (2019)
  • Author(s): Inoue Satoshi、Hirota Yasushi、Ueno Toshihide、十人省略、Tanaka Yosuke、Sakata Seiji、Takeuchi Kengo、Muraoka Ayako、Osuka Satoko、Saito Tsuyoshi、Oda Katsutoshi、Osuga Yutaka、Terao Yasuhisa、Kawazu Masahito、Mano Hiroyuki
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41467-019-13708-y
  • Peer Reviewed / Open Access
• [Presentation] 免疫学的分類によるマイクロサテライト高度不安定性大腸がんの免疫回避機構の解明 (2021)
  • Author(s): 河津正人、岸上史士、波江野洋、石原聡一郎、間野博行
  • Organizer: 第18回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] 全長RNAシーケンスの複数検体統合解析手法の開発と乳がん22検体への応用 (2020)
  • Author(s): 難波真一、上野敏秀、間野博行、河津正人
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] マイクロサテライト高度不安定性大腸がんにおけるクラスI HLA変異解析と免疫学的状態の分類 (2020)
  • Author(s): 河津正人、岸上史士、上野敏秀、波江野洋、石原聡一郎、西川博嘉、間野博行
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] クラスI HLA変異に基づいたマイクロサテライト高度不安定性大腸がんの免疫学的状態の分類 (2020)
  • Author(s): 河津正人、岸上史士、波江野洋、石原聡一郎、西川博嘉、間野博行
  • Organizer: 第24回日本がん免疫学会総会
• [Presentation] 癌cDNA全長シーケンス解析手法の開発と乳がんへの応用 (2018)
  • Author(s): 難波真一、河津正人、上野敏秀、間野博行
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] トリプルネガティブ乳がんにおけるゲノム構造異常の解析 (2018)
  • Author(s): 河津正人
  • Organizer: ゲノムテクノロジー第164委員会 第56回研究会