Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations

Inoue, Satoshi; Hirota, Yasushi; Ueno, Toshihide; Fukui, Yoshikazu; 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

doi:10.1038/s41467-019-13708-y

Cited by 96 publications

(139 citation statements)

References 37 publications

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“…A recent study involving genomic analysis of adenomyosis indicated high variant allele frequencies of KRAS hotspot mutations in the microdissected epithelial cells of adenomyotic tissue, which suggested that adenomyosis may arise from the ectopic proliferation of mutated epithelial cell clones (Inoue et al, 2019). Furthermore, they found identical KRAS mutations in adenomyotic and histologically normal endometrium adjacent to adenomyotic lesions and argued that "KRAS-mutated adenomyotic clones originate from normal endometrium" (Inoue et al, 2019). Our findings of the 3D morphology of adenomyosis support this hypothesis from a histological perspective.…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional understanding of the morphological complexity of the human uterine endometrium

Yamaguchi

Yoshihara

Suda

et al. 2020

Preprint

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The histological basis of the human uterine endometrium has been established by 2D observation. However, the fundamental morphology of endometrial glands is not sufficiently understood because these glands have complicated winding and branching patterns. To construct a big picture of endometrial gland structure, we performed tissue-clearing-based 3D imaging of human uterine endometrial tissue. Our 3D immunohistochemistry and 3D layer analyses revealed that endometrial glands formed a plexus network in the stratum basalis, similar to the rhizome of grass. We then extended our method to assess the 3D morphology of adenomyosis, a representative "endometrium-related disease", and observed 3D morphological features including direct invasion of endometrial glands into the myometrium and an ant colony-like network of ectopic endometrial glands within the myometrium. Thus, 3D analysis of the human endometrium and endometrium-related diseases will be a promising approach to better understand the pathologic physiology of the human endometrium. lives of women from puberty until after menopause (Garcia-Solares et al., 2018;Koninckx et al., 2019;Morice et al., 2016). However, the pathogenesis of endometrium-related diseases remains unclear, and further investigations focusing on the endometrium from the standpoint of disease prevention are required.The conventional morphological theory of endometrial structure has been established based on two-dimensional (2D) histological observation (Johannisson et al., 1982;McLennan and Rydell, 1965;Noyes et al., 1950). Histologically, the endometrium is lined by a simple luminal epithelium and contains tubular glands that radiate through endometrial stroma toward the myometrium via coiling and branching morphogenesis (Gray et al., 2001). The human endometrium is stratified into two zones:the stratum functionalis and the stratum basalis. The stratum functionalis is shed during menstruation and regenerates from an underlying basal layer during the proliferative period. Therefore, it is widely assumed that regeneration of the stratum functionalis depends on endometrial progenitor/stem cells residing in the stratum basalis (Kyo et al., 2011;Maruyama and Yoshimura, 2012;Padykula, 1991;Prianishnikov, 1978). Despite this well-established understanding, neither the detailed mechanisms of endometrial regeneration during the menstrual cycle nor the localization of endometrial progenitor/stem cells have been fully characterized (Garry et al., 2010;Gellersen and Brosens, 2014;Santamaria et al., 2018). One of the reasons for this knowledge gap is that the fundamental structure of the human endometrium has not been sufficiently clarified. Since human endometrial glands have complicated winding and branching morphologies, it is extremely difficult to assess the whole shapes of glands by only 2D histopathology imaging.In our previous genomic study, sequence analysis of 109 single endometrial glands revealed that each gland carried distinct somatic mutations in cancer-associated genes such as PIK3CA, KRAS...

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Section: Discussionmentioning

confidence: 99%

Three-dimensional understanding of the morphological complexity of the human uterine endometrium

Yamaguchi

Yoshihara

Suda

et al. 2020

Preprint

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“…Recent advances in next-generation sequencing (NGS) have allowed deep sequencing of human cancers, precancerous epithelium, and lesions previously considered to be non-neoplastic, such as endometriosis, 1,2 uterine adenomyosis, 3 and brain arteriovenous malformations. 4 NGS detects oncogenic mutations even in small cell populations.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological and molecular analyses of linearly expanded epithelial cells with β‐catenin alterations, “β‐catenin signature”, in the normal fallopian tube

et al. 2020

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Clinicopathological and molecular analyses of linearly expanded epithelial cells with b-catenin alterations, "b-catenin signature", in the normal fallopian tube Aims: Recent advances in next-generation sequencing have made it clear that clonal expansion of cells harbouring driver gene mutations occurs in physiologically normal epithelium. Molecular analysis of tubal epithelium has been almost exclusively confined to the TP53 pathway, which is involved in serous carcinogenesis. Other oncogenic events have not been explored in detail. Here, we report the linear expansion of fallopian tubal epithelial cells exhibiting an altered b-catenin profile (b-catenin signature). Through molecular analyses, we determined the incidence and clinicopathological significance of b-catenin signatures. Methods and results: We evaluated 64 specimens of surgically removed bilateral fallopian tubes. Thirty-three b-catenin signatures were identified in 13 cases (20.3%); these patients were significantly younger than those without b-catenin signatures (median ages of 44 and 57 years, respectively, P = 0.0317). No correlation between b-catenin signature and any clinical factor was observed. CTNNB1 mutations were detected in three of eight b-catenin signatures when tissues were microdissected and subjected to Sanger sequencing in two representative cases. Conclusions: This is the first report of the CTNNB1 mutation in clusters of morphologically bland tubal epithelial cells. The results of this study indicate that b-catenin signatures are common, and they may be a part of diverse molecular alterations occurring in normal tubal epithelium.

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“…External physical/mechanical factors such as caesarean section can induce reactions that trigger genomic alterations in NE. Notably, recurrent mutations affecting KRAS and PIK3CA have been reported in NE [3][4][5][6] . Increased age, high body mass index and parity may be associated with a burden of mutations in NE 4,5 .…”

mentioning

confidence: 99%

“…Endometrium-like epithelial cells that ectopically proliferate in normal myometrium (NM). Mutation of KRAS and/or PIK3CA in NE is the earliest events in the molecular pathogenesis of adenomyosis 3 . It has been shown that parity, spontaneous abortion and smoking could be risk factors for adenomyosis 7,8 .…”

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confidence: 99%