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 OdaYutaka Osuga, Yasuhisa Terao, Masahito Kawazu, Hiroyuki Mano

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

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.

Original languageEnglish
Article number5785
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

Fingerprint

Dive into the research topics of 'Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations'. Together they form a unique fingerprint.

Cite this