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Elucidation of pathogenesis of endometriosis and endometriosis-associated ovarian cancer based on genomic analyses for normal endometrium

Research Project

Project/Area Number 20H03821
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 56040:Obstetrics and gynecology-related
Research InstitutionNiigata University

Principal Investigator

ENOMOTO Takayuki  新潟大学, 医歯学系, 特任教授 (90283754)

Co-Investigator(Kenkyū-buntansha) 井ノ上 逸朗  国立遺伝学研究所, ゲノム・進化研究系, 教授 (00192500)
吉原 弘祐  新潟大学, 医歯学系, 教授 (40547535)
安達 聡介  新潟大学, 医歯学総合病院, 助教 (50613147)
田村 亮  新潟大学, 医歯学総合病院, 助教 (70650620)
石黒 竜也  新潟大学, 医歯学総合病院, 助教 (80625690)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2022: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Keywords正常子宮内膜 / 子宮内膜症 / 内膜症関連卵巣癌 / ゲノム / 癌関連遺伝子
Outline of Research at the Start

我々は、これまで内膜症関連卵巣癌の原因と考えられていたPIK3CA・KRAS などの癌関連遺伝子が、すでに子宮内膜症や正常子宮内膜で高頻度に体細胞変異を起こしていること、癌関連遺伝子変異は子宮内膜上皮・内膜症上皮に認めるが、子宮内膜間質・内膜症間質に認めないこと、を世界に先駆けて報告している。本研究では、先行研究を発展させ、正常子宮内膜から子宮内膜症・内膜症関連癌発症に至るまでの連続的なゲノム異常に着目し、正常子宮内膜から子宮内膜症および内膜症関連卵巣癌の発症に至る進展メカニズムを解明することを目的とし、最終的に、子宮内膜症および内膜症関連卵巣癌の発症予防を目指す。

Outline of Final Research Achievements

Genomic analysis of normal endometrium was performed at a wide range of ages. Genomic aberrations in normal endometrium were positively correlated with age and cumulative number of menstrual cycles. Genomic analysis of normal endometrium also revealed that endometrial glands with cancer-associated genetic mutations showed an advantageous spread in the endometrium. Furthermore, combination of 3D structural analysis of the endometrium with genomic analysis uncovered that each gland arising from the endometrial rhizome structure was monoclonal and shared the same genomic alterations, indicating that the rhizome structure plays an important role in shaping the spatial spread of cancer-associated genes in the endometrium.

Academic Significance and Societal Importance of the Research Achievements

現代女性の月経回数は100年前に比べて9倍以上増加しており、子宮内膜が受けるストレスが増大している。そのため、子宮内膜関連疾患が増加傾向にあり、女性のQOLを低下させてしまう。本研究では、子宮内膜関連疾患の発症を予防する方法を検討する上で非常に重要な知見であり、新規予防法あるいは早期発見法を開発することで社会に還元していくことが可能である。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (26 results)

All 2023 2022 2021 2020

All Journal Article (24 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 18 results,  Open Access: 14 results) Presentation (2 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] Awareness of Infectious Disease Screening During Early Pregnancy and Knowledge About its Vertical Transmission in Japan: A Report from the Pregnant Women Health Initiative2023

    • Author(s)
      Odagami Mizuha、..., Takayuki Enomoto, et al.
    • Journal Title

      Maternal and Child Health Journal

      Volume: 27 Issue: 5 Pages: 933-943

    • DOI

      10.1007/s10995-023-03597-5

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Trends and characteristics of fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer in Japan: a survey by the Gynecologic Oncology Committee of the Japan Society of Obstetrics and Gynecology2023

    • Author(s)
      Ushijima Kimio、Tsuda Naotake、Yamagami Wataru、Mitsuhashi Akira、Mikami Mikio、Yaegashi Nobuo、Enomoto Takayuki
    • Journal Title

      Journal of Gynecologic Oncology

      Volume: 34 Issue: 3

    • DOI

      10.3802/jgo.2023.34.e38

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Prognostic relevance of HRDness gene expression signature in ovarian high-grade serous carcinoma; JGOG3025-TR2 study2023

    • Author(s)
      Takamatsu Shiro、Yoshihara Kosuke、Baba Tsukasa、Shimada Muneaki、Yoshida Hiroshi、Kajiyama Hiroaki、Oda Katsutoshi、Mandai Masaki、Okamoto Aikou、Enomoto Takayuki、Matsumura Noriomi
    • Journal Title

      British Journal of Cancer

      Volume: 128 Issue: 6 Pages: 1095-1104

    • DOI

      10.1038/s41416-022-02122-9

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of adjuvant chemotherapy on the overall survival of patients with resectable bulky small cell neuroendocrine cervical cancer: a JSGO-JSOG joint study2023

    • Author(s)
      Seino Manabu、Nagase Satoru、Ohta Tsuyoshi、Yamagami Wataru、Ebina Yasuhiko、Kobayashi Yoichi、Tabata Tsutomu、Kaneuchi Masanori、Enomoto Takayuki、Mikami Mikio
    • Journal Title

      Journal of Gynecologic Oncology

      Volume: 34 Issue: 1

    • DOI

      10.3802/jgo.2023.34.e4

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endometrial carcinosarcoma2022

    • Author(s)
      Bogani Giorgio, ..., Takayuki Enomoto, et al.
    • Journal Title

      International Journal of Gynecologic Cancer

      Volume: 33 Issue: 2 Pages: 147-174

    • DOI

      10.1136/ijgc-2022-004073

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Veliparib with frontline chemotherapy and as maintenance in Japanese women with ovarian cancer: a subanalysis of efficacy, safety, and antiemetic use in the phase 3 VELIA trial2022

    • Author(s)
      Mizuno Mika、..., Takayuki Enomoto, et al.
    • Journal Title

      International Journal of Clinical Oncology

      Volume: 28 Issue: 1 Pages: 163-174

    • DOI

      10.1007/s10147-022-02258-x

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Factor structure of the parental bonding instrument for pregnant Japanese women2022

    • Author(s)
      Fukui Naoki、Watanabe Yuichiro、Hashijiri Koyo、Motegi Takaharu、Ogawa Maki、Egawa Jun、Enomoto Takayuki、Someya Toshiyuki
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 19071-19071

    • DOI

      10.1038/s41598-022-22017-2

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Japanese nationwide observational multicenter study of tumor <i>BRCA1</i> / <i>2</i> variant testing in advanced ovarian cancer2022

    • Author(s)
      Oda Katsutoshi、Aoki Daisuke、Tsuda Hitoshi、Nishihara Hiroshi、Aoyama Hisanori、Inomata Hyoe、Shimada Muneaki、Enomoto Takayuki
    • Journal Title

      Cancer Science

      Volume: 114 Issue: 1 Pages: 271-280

    • DOI

      10.1111/cas.15518

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Incidence of gastrointestinal perforation associated with bevacizumab in combination with neoadjuvant chemotherapy as first-line treatment of advanced ovarian, fallopian tube, or peritoneal cancer: analysis of a Japanese healthcare claims database2022

    • Author(s)
      Ueda Akihiko、Watari Hidemichi、Mandai Masaki、Fukuhara Shunichi、Sugitani Yasuo、Ogino Kiyoko、Kamijima Shuichi、Enomoto Takayuki
    • Journal Title

      Journal of Gynecologic Oncology

      Volume: 33 Issue: 6

    • DOI

      10.3802/jgo.2022.33.e78

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Comparison of global treatment guidelines for locally advanced cervical cancer to optimize best care practices: A systematic and scoping review2022

    • Author(s)
      Pujade-Lauraine Eric、Tan David S.P.、Leary Alexandra、Mirza Mansoor Raza、Enomoto Takayuki、Takyar Jitender、Nunes Ana Tablante、Chag?i Jos? David Hern?ndez、Paskow Michael J.、Monk Bradley J.
    • Journal Title

      Gynecologic Oncology

      Volume: 167 Issue: 2 Pages: 360-372

    • DOI

      10.1016/j.ygyno.2022.08.013

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Problems with catch-up HPV vaccination after resumption of proactive recommendations2022

    • Author(s)
      Sekine Masayuki、Yamaguchi Manako、Kudo Risa、Hanley Sharon J B、Ueda Yutaka、Kurosawa Megumi、Adachi Sosuke、Miyagi Etsuko、Hara Megumi、Enomoto Takayuki
    • Journal Title

      The Lancet Oncology

      Volume: 23 Issue: 8 Pages: 972-973

    • DOI

      10.1016/s1470-2045(22)00259-5

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Current status of hereditary breast and ovarian cancer practice among gynecologic oncologists in Japan: a nationwide survey by the Japan Society of Gynecologic Oncology (JSGO)2022

    • Author(s)
      Kobayashi Y, Masuda K, Hiraswa A, Takehara K, Tsuda H, Watanabe Y, Oda K, Nagase S, Mandai M, Okamoto A, Yaegashi N, Mikami M, Enomoto T, Aoki D, Katabuchi H; Working Group on Clinical Practice for Cancer Genomic Medicine and HBOC, Japan Society of Gynecologic Oncology.
    • Journal Title

      J Gynecol Oncol.

      Volume: 33 Issue: 5

    • DOI

      10.3802/jgo.2022.33.e61

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Change of HPV vaccination rates in Japan: the effect of individual notifications implemented by local governments2022

    • Author(s)
      Yagi Asami、Ueda Yutaka、Nakagawa Satoshi、Ikeda Sayaka、Kakuda Mamoru、Hiramatsu Kosuke、Miyoshi Ai、Kobayashi Eiji、Kimura Toshihiro、Hirai Kei、Nakayama Tomio、Miyagi Etsuko、Sekine Masayuki、Enomoto Takayuki、Kimura Tadashi
    • Journal Title

      International Journal of Clinical Oncology

      Volume: 27 Issue: 10 Pages: 1651-1659

    • DOI

      10.1007/s10147-022-02213-w

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effectiveness of human papillomavirus vaccine against cervical precancer in Japan: Multivariate analyses adjusted for sexual activity2022

    • Author(s)
      Kudo Risa、Sekine Masayuki、Yamaguchi Manako、Hara Megumi、Hanley Sharon J. B.、Kurosawa Megumi、Adachi Sosuke、Ueda Yutaka、Miyagi Etsuko、Ikeda Sayaka、Yagi Asami、Enomoto Takayuki
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 9 Pages: 3211-3220

    • DOI

      10.1111/cas.15471

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lenvatinib plus pembrolizumab in Japanese patients with endometrial cancer: Results from Study 309/ KEYNOTE7752022

    • Author(s)
      Yonemori Kan、Yunokawa Mayu、Ushijima Kimio、Sakata Jun、Shikama Ayumi、Minobe Shinichiro、Usami Tomoka、Enomoto Takayuki、Takehara Kazuhiro、Hasegawa Kosei、Yamagami Wataru、Yamamoto Keiko、Han Shirong、Dutta Lea、Orlowski Robert、Miura Takuma、Makker Vicky、Fujiwara Keiichi
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 10 Pages: 3489-3497

    • DOI

      10.1111/cas.15436

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Surgical skill and oncological outcome of laparoscopic radical hysterectomy: JGOG1081s-A1, an ancillary analysis of the Japanese Gynecologic Oncology Group Study JGOG10812022

    • Author(s)
      Kobayashi Eiji、...、Enomoto Takayuki
    • Journal Title

      Gynecologic Oncology

      Volume: - Issue: 2 Pages: 293-301

    • DOI

      10.1016/j.ygyno.2022.02.005

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adjuvant Chemotherapy for Endometrial Cancer (ACE) trial: A randomized phase II study for advanced endometrial carcinoma2022

    • Author(s)
      Egawa‐Takata Tomomi、 ' 、Kimura Tadashi
    • Journal Title

      Cancer Science

      Volume: - Issue: 5 Pages: 1693-1701

    • DOI

      10.1111/cas.15310

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium2022

    • Author(s)
      Yamaguchi Manako、Nakaoka Hirofumi、Suda Kazuaki、Yoshihara Kosuke、Ishiguro Tatsuya、Yachida Nozomi、Saito Kyota、Ueda Haruka、Sugino Kentaro、Mori Yutaro、Yamawaki Kaoru、Tamura Ryo、Revathidevi Sundaramoorthy、Motoyama Teiichi、Tainaka Kazuki、Verhaak Roel G. W.、Inoue Ituro、Enomoto Takayuki
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 943-943

    • DOI

      10.1038/s41467-022-28568-2

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] <sup>18</sup>F-FDG Fetal Dosimetry Calculated with PET/MRI2022

    • Author(s)
      Zanotti-Fregonara Paolo、Ishiguro Tatsuya、Yoshihara Kosuke、Ishii Shiro、Enomoto Takayuki
    • Journal Title

      Journal of Nuclear Medicine

      Volume: - Issue: 10 Pages: 1592-1597

    • DOI

      10.2967/jnumed.121.263561

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Three-dimensional understanding of the morphological complexity of the human uterine endometrium2021

    • Author(s)
      Yamaguchi Manako、Yoshihara Kosuke、Suda Kazuaki、Nakaoka Hirofumi、Yachida Nozomi、Ueda Haruka、Sugino Kentaro、Mori Yutaro、Yamawaki Kaoru、Tamura Ryo、Ishiguro Tatsuya、Motoyama Teiichi、Watanabe Yu、Okuda Shujiro、Tainaka Kazuki、Enomoto Takayuki
    • Journal Title

      iScience

      Volume: 24 Issue: 4 Pages: 102258-102258

    • DOI

      10.1016/j.isci.2021.102258

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biological significance of KRAS mutant allele expression in ovarian endometriosis2021

    • Author(s)
      Yachida Nozomi、Yoshihara Kosuke、Suda Kazuaki、Nakaoka Hirofumi、Ueda Haruka、Sugino Kentaro、Yamaguchi Manako、Mori Yutaro、Yamawaki Kaoru、Tamura Ryo、Ishiguro Tatsuya、Kase Hiroaki、Motoyama Teiichi、Enomoto Takayuki
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 5 Pages: 2020-2032

    • DOI

      10.1111/cas.14871

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of in vitro 3D spheroid cell cultivation from human gynecologic cancer tissues2021

    • Author(s)
      Ueda Haruka、Mori Yutaro、Yamawaki Kaoru、Ishiguro Tatsuya、Ohata Hirokazu、Sato Ai、Sugino Kentaro、Yachida Nozomi、Yamaguchi Manako、Suda Kazuaki、Tamura Ryo、Yoshihara Kosuke、Okamoto Koji、Enomoto Takayuki
    • Journal Title

      STAR Protocols

      Volume: 2 Issue: 1 Pages: 100354-100354

    • DOI

      10.1016/j.xpro.2021.100354

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss-of-function mutations: implication for the two-hit hypothesis2020

    • Author(s)
      Yachida Nozomi、Yoshihara Kosuke、Suda Kazuaki、Nakaoka Hirofumi、Ueda Haruka、Sugino Kentaro、Yamaguchi Manako、Mori Yutaro、Yamawaki Kaoru、Tamura Ryo、Ishiguro Tatsuya、Isobe Masanori、Motoyama Teiichi、Inoue Ituro、Enomoto Takayuki
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 14260-14260

    • DOI

      10.1038/s41598-020-71273-7

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The post-progression survival of patients with recurrent or persistent ovarian clear cell carcinoma: results from a randomized phase III study in JGOG3017/GCIG2020

    • Author(s)
      Kondo Eiji、Tabata Tsutomu、Suzuki Nao、Aoki Daisuke、Yahata Hideaki、Kotera Yoshio、Tokuyama Osamu、Fujiwara Keiichi、Kimura Eizo、Terauchi Fumitoshi、Sumi Toshiyuki、Okamoto Aikou、Yaegashi Nobuo、Enomoto Takayuki、Sugiyama Toru
    • Journal Title

      Journal of Gynecologic Oncology

      Volume: 31 Issue: 6

    • DOI

      10.3802/jgo.2020.31.e94

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 3D structure and molecular heterogeneity in normal uterine endometrium2021

    • Author(s)
      Takayuki Enomoto, Kosuke Yoshihara
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The naughty genes and 3D structure of the endometrium2021

    • Author(s)
      Takayuki Enomoto, Manako Yamaguchi, Kosuke Yoshihara
    • Organizer
      ESHRE 2021 Virtual
    • Related Report
      2021 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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