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Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations

Author

Listed:
  • Satoshi Inoue

    (The University of Tokyo
    National Cancer Center Research Institute)

  • Yasushi Hirota

    (The University of Tokyo)

  • Toshihide Ueno

    (National Cancer Center Research Institute)

  • Yamato Fukui

    (The University of Tokyo)

  • Emiko Yoshida

    (Juntendo University Faculty of Medicine)

  • Takuo Hayashi

    (Juntendo University Faculty of Medicine)

  • Shinya Kojima

    (National Cancer Center Research Institute)

  • Reina Takeyama

    (National Cancer Center Research Institute)

  • Taiki Hashimoto

    (National Cancer Center Hospital)

  • Tohru Kiyono

    (National Cancer Center Research Institute)

  • Masako Ikemura

    (The University of Tokyo)

  • Ayumi Taguchi

    (The University of Tokyo)

  • Tomoki Tanaka

    (The University of Tokyo)

  • Yosuke Tanaka

    (National Cancer Center Research Institute)

  • Seiji Sakata

    (The Cancer Institute, Japanese Foundation for Cancer Research)

  • Kengo Takeuchi

    (The Cancer Institute, Japanese Foundation for Cancer Research
    The Cancer Institute, Japanese Foundation for Cancer Research
    The Cancer Institute, Japanese Foundation for Cancer Research)

  • Ayako Muraoka

    (Nagoya University Graduate School of Medicine)

  • Satoko Osuka

    (Nagoya University Graduate School of Medicine)

  • Tsuyoshi Saito

    (Juntendo University Faculty of Medicine)

  • Katsutoshi Oda

    (The University of Tokyo)

  • Yutaka Osuga

    (The University of Tokyo)

  • Yasuhisa Terao

    (Juntendo University Faculty of Medicine)

  • Masahito Kawazu

    (The University of Tokyo
    National Cancer Center Research Institute)

  • Hiroyuki Mano

    (National Cancer Center Research Institute)

Abstract

Uterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life. The genomic features of adenomyosis are unknown. Here we apply next-generation sequencing to adenomyosis (70 individuals and 192 multi-regional samples), as well as co-occurring leiomyoma and endometriosis, and find recurring KRAS mutations in 26/70 (37.1%) of adenomyosis cases. Multi-regional sequencing reveals oligoclonality in adenomyosis, with some mutations also detected in normal endometrium and/or co-occurring endometriosis. KRAS mutations are more frequent in cases of adenomyosis with co-occurring endometriosis, low progesterone receptor (PR) expression, or progestin (dienogest; DNG) pretreatment. DNG’s anti-proliferative effect is diminished via epigenetic silencing of PR in immortalized cells with mutant KRAS. Our genomic analyses suggest that adenomyotic lesions frequently contain KRAS mutations that may reduce DNG efficacy, and that adenomyosis and endometriosis may share molecular etiology, explaining their co-occurrence. These findings could lead to genetically guided therapy and/or relapse risk assessment after uterine-sparing surgery.

Suggested Citation

  • Satoshi Inoue & Yasushi Hirota & Toshihide Ueno & Yamato Fukui & Emiko Yoshida & Takuo Hayashi & Shinya Kojima & Reina Takeyama & Taiki Hashimoto & Tohru Kiyono & Masako Ikemura & Ayumi Taguchi & Tomo, 2019. "Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13708-y
    DOI: 10.1038/s41467-019-13708-y
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    Cited by:

    1. Manako Yamaguchi & Hirofumi Nakaoka & Kazuaki Suda & Kosuke Yoshihara & Tatsuya Ishiguro & Nozomi Yachida & Kyota Saito & Haruka Ueda & Kentaro Sugino & Yutaro Mori & Kaoru Yamawaki & Ryo Tamura & Sun, 2022. "Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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