Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations

Satoshi Inoue,Ayako Muraoka,Satoko Osuka,Yosuke Tanaka,Ayumi Taguchi,Toshihide Ueno,Yasuhisa Terao,Kengo Takeuchi,Reina Takeyama,Tsuyoshi Saito,Shinya Kojima,Taiki Hashimoto,Yutaka Osuga,Tohru Kiyono,Emiko Yoshida,Masahito Kawazu,Yoshikazu Fukui ,Yasushi Hirota,Seiji Sakata,Masako Ikemura,Takuo Hayashi,Katsutoshi Oda,Tomoki Tanaka,Hiroyuki Mano

doi:10.1038/s41467-019-13708-y

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.

Highlights

Uterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life
We collected fresh-frozen samples from 70 individuals: a discovery cohort of 51 adenomyosis patients whose samples were subjected to whole exome sequencing (WES), plus an additional 19 individuals who were biopsied at a later time and whose samples were subjected to targeted deep sequencing (TDS) (Supplementary Data 1 and 2)
In 29 of these 70 individuals, multi-regional sampling of adenomyosis with/ without co-existing endometriosis and leiomyoma was performed and adjacent normal tissues were collected (Supplementary Fig. 1 and Supplementary Data 3)

Summary

Introduction

Uterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life. KRAS mutations are more frequent in cases of adenomyosis with co-occurring endometriosis, low progesterone receptor (PR) expression, or progestin (dienogest; DNG) pretreatment. 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. Adenomyosis and endometriosis are closely linked diseases, as both are estrogendependent and often co-exist in the same patients[3,4,5] This cooccurrence is a risk factor for relapse in women who have undergone fertility sparing surgery[6,7,8]. Adenomyotic symptoms are currently relieved using either endocrine therapies based on gonadotrophin-releasing hormone agonist (GnRHa) or progestins such as dienogest (DNG), or by employing a levonorgestrel-releasing intrauterine system (LNG-IUS)[16,17]

Methods

Results

Conclusion