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, Hiroyuki Mano
Nature communications · 2019 · vol. 10(1) , pp. 5785 · doi:10.1038/s41467-019-13708-y · PMID:31857578 · PMC6923389 · W2996540178
article OA: gold CC0 ⤵ 91 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

This study found recurring KRAS mutations in 37.1% of uterine adenomyosis cases, indicating oligoclonality and potential shared etiology with endometriosis, which may impact treatment efficacy.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

Inoue et al. used next-generation sequencing to profile adenomyosis in 70 individuals (whole-exome sequencing plus targeted deep sequencing) and included multi-regional sampling from selected cases with co-occurring endometriosis and/or leiomyoma, along with adjacent normal tissues and germline controls. They found that adenomyosis lesions are oligoclonal and that recurrent activating KRAS p.G12 mutations were present in 26/70 (37.1%) adenomyosis cases, with some KRAS alterations also detected in histologically normal endometrium and/or co-occurring endometriosis. KRAS mutation frequency was higher in adenomyosis cases with co-existing endometriosis, low progesterone receptor expression, and prior dienogest (DNG) treatment, and they report functional evidence that mutant KRAS reduces DNG anti-proliferative effects via epigenetic PR silencing in immortalized cells. A stated limitation is that their WES depth and variant filtering criteria may miss other low–variant allele frequency driver mutations. This paper is centrally about adenomyosis—demonstrating oligoclonality and recurring KRAS mutations in uterine adenomyosis, and linking adenomyosis molecularly to endometriosis.

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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.

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Condition tags

endometriosisadenomyosis

MeSH descriptors

Adenomyosis Endometriosis Nandrolone Proto-Oncogene Proteins p21(ras) Adenomyosis Adenomyosis Adenomyosis Adult Cell Proliferation Cell Proliferation Cell Proliferation DNA Mutational Analysis Endometriosis Endometriosis Endometriosis Endometrium Endometrium Endometrium Female High-Throughput Nucleotide Sequencing

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