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Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations

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-occu...

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Autores principales: Inoue, Satoshi, Hirota, Yasushi, Ueno, Toshihide, Fukui, Yamato, Yoshida, Emiko, Hayashi, Takuo, Kojima, Shinya, Takeyama, Reina, Hashimoto, Taiki, Kiyono, Tohru, Ikemura, Masako, Taguchi, Ayumi, Tanaka, Tomoki, Tanaka, Yosuke, Sakata, Seiji, Takeuchi, Kengo, Muraoka, Ayako, Osuka, Satoko, Saito, Tsuyoshi, Oda, Katsutoshi, Osuga, Yutaka, Terao, Yasuhisa, Kawazu, Masahito, Mano, Hiroyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923389/
https://www.ncbi.nlm.nih.gov/pubmed/31857578
http://dx.doi.org/10.1038/s41467-019-13708-y
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author Inoue, Satoshi
Hirota, Yasushi
Ueno, Toshihide
Fukui, Yamato
Yoshida, Emiko
Hayashi, Takuo
Kojima, Shinya
Takeyama, Reina
Hashimoto, Taiki
Kiyono, Tohru
Ikemura, Masako
Taguchi, Ayumi
Tanaka, Tomoki
Tanaka, Yosuke
Sakata, Seiji
Takeuchi, Kengo
Muraoka, Ayako
Osuka, Satoko
Saito, Tsuyoshi
Oda, Katsutoshi
Osuga, Yutaka
Terao, Yasuhisa
Kawazu, Masahito
Mano, Hiroyuki
author_facet Inoue, Satoshi
Hirota, Yasushi
Ueno, Toshihide
Fukui, Yamato
Yoshida, Emiko
Hayashi, Takuo
Kojima, Shinya
Takeyama, Reina
Hashimoto, Taiki
Kiyono, Tohru
Ikemura, Masako
Taguchi, Ayumi
Tanaka, Tomoki
Tanaka, Yosuke
Sakata, Seiji
Takeuchi, Kengo
Muraoka, Ayako
Osuka, Satoko
Saito, Tsuyoshi
Oda, Katsutoshi
Osuga, Yutaka
Terao, Yasuhisa
Kawazu, Masahito
Mano, Hiroyuki
author_sort Inoue, Satoshi
collection PubMed
description 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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spelling pubmed-69233892019-12-22 Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations Inoue, Satoshi Hirota, Yasushi Ueno, Toshihide Fukui, Yamato Yoshida, Emiko Hayashi, Takuo Kojima, Shinya Takeyama, Reina Hashimoto, Taiki Kiyono, Tohru Ikemura, Masako Taguchi, Ayumi Tanaka, Tomoki Tanaka, Yosuke Sakata, Seiji Takeuchi, Kengo Muraoka, Ayako Osuka, Satoko Saito, Tsuyoshi Oda, Katsutoshi Osuga, Yutaka Terao, Yasuhisa Kawazu, Masahito Mano, Hiroyuki Nat Commun Article 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. Nature Publishing Group UK 2019-12-19 /pmc/articles/PMC6923389/ /pubmed/31857578 http://dx.doi.org/10.1038/s41467-019-13708-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Inoue, Satoshi
Hirota, Yasushi
Ueno, Toshihide
Fukui, Yamato
Yoshida, Emiko
Hayashi, Takuo
Kojima, Shinya
Takeyama, Reina
Hashimoto, Taiki
Kiyono, Tohru
Ikemura, Masako
Taguchi, Ayumi
Tanaka, Tomoki
Tanaka, Yosuke
Sakata, Seiji
Takeuchi, Kengo
Muraoka, Ayako
Osuka, Satoko
Saito, Tsuyoshi
Oda, Katsutoshi
Osuga, Yutaka
Terao, Yasuhisa
Kawazu, Masahito
Mano, Hiroyuki
Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
title Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
title_full Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
title_fullStr Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
title_full_unstemmed Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
title_short Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations
title_sort uterine adenomyosis is an oligoclonal disorder associated with kras mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923389/
https://www.ncbi.nlm.nih.gov/pubmed/31857578
http://dx.doi.org/10.1038/s41467-019-13708-y
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