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

doi:10.1038/s41467-019-13708-y

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 journal › Article › peer-review

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 language	English
Article number	5785
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13708-y
Publication status	Published - 2019 Dec 1
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-019-13708-y

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Inoue, S., Hirota, Y., Ueno, T., Fukui, Y., Yoshida, E., Hayashi, T., Kojima, S., Takeyama, R., Hashimoto, T., Kiyono, T., Ikemura, M., Taguchi, A., Tanaka, T., Tanaka, Y., Sakata, S., Takeuchi, K., Muraoka, A., Osuka, S., Saito, T., ... Mano, H. (2019). Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations. Nature communications, 10(1), [5785]. https://doi.org/10.1038/s41467-019-13708-y

Inoue, S, Hirota, Y, Ueno, T, Fukui, Y, Yoshida, E, Hayashi, T, Kojima, S, Takeyama, R, Hashimoto, T, Kiyono, T, Ikemura, M, Taguchi, A, Tanaka, T, Tanaka, Y, Sakata, S, Takeuchi, K, Muraoka, A, Osuka, S, Saito, T, Oda, K, Osuga, Y, Terao, Y, Kawazu, M & Mano, H 2019, 'Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations', Nature communications, vol. 10, no. 1, 5785. https://doi.org/10.1038/s41467-019-13708-y

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title = "Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations",

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{\textquoteright}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.",

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

note = "Funding Information: We thank members of Dr Mano{\textquoteright}s lab, particularly Dr Shinji Kohsaka and Ms Takako Matsumoto, and National Cancer Center Research Institute Core Facility, particularly Ms Yuriya Shiotani and Mr Naoaki Uchiya, for their expert technical support. We are grateful to Drs Kelsie Thu and David Cescon for their constructive suggestions. We thank Ms. Chiho Kohno for her technical assistance and Dr. Hiroyuki Miyoshi (RIKEN, BioResource Center; presently Keio University) for providing plasmids. We also thank Dr Momoe Itsumi for her cooperation in creating original illustrations showing in Figs. 3 and 4, and Supplementary Figs. 13D and 15A, C. We are also grateful to all the women who have generously donated their tissues to be used in our research studies; without them, this work would not have been possible. This study was supported in part by JSPS KAKENHI grants (#19K07708 to S.I., #19H03144 to Y.H., #17K07250 to T.U., #19H03796 to Y.O., and #18K09299 to Y.T.E.); a grant for Leading Advanced Projects for Medical Innovation (LEAP) (#JP17am0001001h0004 to H.M.); Project for Cancer Research and Therapeutic Evolution (P-CREATE) (#JP19cm0106502 to M.K.), and Project for “Whole Implementation to Support and Ensure the female life” (WISE) (#JP19gk0210021h0001 to Y.H.) from the Japanese Agency for Medical Research and Development; and a grant from Suzuken Memorial Foundation (to S.I.). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-13708-y",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations

AU - Inoue, Satoshi

AU - Hirota, Yasushi

AU - Ueno, Toshihide

AU - Fukui, Yamato

AU - Yoshida, Emiko

AU - Hayashi, Takuo

AU - Kojima, Shinya

AU - Takeyama, Reina

AU - Hashimoto, Taiki

AU - Kiyono, Tohru

AU - Ikemura, Masako

AU - Taguchi, Ayumi

AU - Tanaka, Tomoki

AU - Tanaka, Yosuke

AU - Sakata, Seiji

AU - Takeuchi, Kengo

AU - Muraoka, Ayako

AU - Osuka, Satoko

AU - Saito, Tsuyoshi

AU - Oda, Katsutoshi

AU - Osuga, Yutaka

AU - Terao, Yasuhisa

AU - Kawazu, Masahito

AU - Mano, Hiroyuki

N1 - Funding Information: We thank members of Dr Mano’s lab, particularly Dr Shinji Kohsaka and Ms Takako Matsumoto, and National Cancer Center Research Institute Core Facility, particularly Ms Yuriya Shiotani and Mr Naoaki Uchiya, for their expert technical support. We are grateful to Drs Kelsie Thu and David Cescon for their constructive suggestions. We thank Ms. Chiho Kohno for her technical assistance and Dr. Hiroyuki Miyoshi (RIKEN, BioResource Center; presently Keio University) for providing plasmids. We also thank Dr Momoe Itsumi for her cooperation in creating original illustrations showing in Figs. 3 and 4, and Supplementary Figs. 13D and 15A, C. We are also grateful to all the women who have generously donated their tissues to be used in our research studies; without them, this work would not have been possible. This study was supported in part by JSPS KAKENHI grants (#19K07708 to S.I., #19H03144 to Y.H., #17K07250 to T.U., #19H03796 to Y.O., and #18K09299 to Y.T.E.); a grant for Leading Advanced Projects for Medical Innovation (LEAP) (#JP17am0001001h0004 to H.M.); Project for Cancer Research and Therapeutic Evolution (P-CREATE) (#JP19cm0106502 to M.K.), and Project for “Whole Implementation to Support and Ensure the female life” (WISE) (#JP19gk0210021h0001 to Y.H.) from the Japanese Agency for Medical Research and Development; and a grant from Suzuken Memorial Foundation (to S.I.). Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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ER -

Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations

Abstract

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