Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations

Satoshi Inoue (), Yasushi Hirota, Toshihide Ueno, Yamato Fukui, Emiko Yoshida, Takuo Hayashi, Shinya Kojima, Reina Takeyama, Taiki Hashimoto, Tohru Kiyono, Masako Ikemura, Ayumi Taguchi, Tomoki Tanaka, Yosuke Tanaka, Seiji Sakata, Kengo Takeuchi, Ayako Muraoka, Satoko Osuka, Tsuyoshi Saito, Katsutoshi Oda, Yutaka Osuga, Yasuhisa Terao, Masahito Kawazu and Hiroyuki Mano
Additional contact information
Satoshi Inoue: The University of Tokyo
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
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
Hiroyuki Mano: National Cancer Center Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13708-y

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