Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium

Suda, Kazuaki; Nakaoka, Hirofumi; Yoshihara, Kosuke; Ishiguro, Takehiko; Tamura, Ryo; Mori, Yutaro; Yamawaki, Kaoru; Adachi, Sosuke; Takahashi, Tomoko; Kase, Hiroaki; Tanaka, Kenichi; Yamamoto, Tadashi; Motoyama, Teiichi; Inoue, Ituro; Enomoto, Takayuki

doi:10.1016/j.celrep.2018.07.037

Cited by 342 publications

(436 citation statements)

References 64 publications

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“…This hypothesis seems well supported by two recent studies wherein individual endometrial glands were laser-captured from different areas within the endometrium of the same patient. Both studies suggest that different glands harbored different mutations [34,35]. These studies and our own results are also consistent with the findings by Mutter et al (2014) [20],where PTEN-loss appears zonally in single, or small clusters of, glands (Supplementary Figure S1).…”

Section: Discussionsupporting

confidence: 92%

“…These studies and our own results are also consistent with the findings by Mutter et al (2014) [20],where PTEN-loss appears zonally in single, or small clusters of, glands (Supplementary Figure S1). Therefore, although our study represents broader sampling of the endometrium and mutations, our observations and those of others [34,35] are consistent with driver mutations, such as KRAS G12 mutations, occurring in small, clonal pockets throughout the uterus. Furthermore, it seems likely that acquisition of these mutations provides sufficient selective advantages to expand within an entire gland of affected endometrial cells, allowing this population to be detectable by our methods.…”

Section: Discussionsupporting

confidence: 88%

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Oncogenic Mutations in Histologically Normal Endometrium: The New Normal?

Lac

Nazeran

Tessier‐Cloutier

et al. 2019

Preprint

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The presence of somatic driver mutations in endometriosis has previously been believed to represent early events in transformation, however our group and others have described such mutations in roughly one-third of cases of deep infiltrating or iatrogenic endometriosis. These forms of endometriosis rarely progress to malignancy. Recent studies have also shown somatic driver mutations in normal skin, blood, peritoneal washings, and esophageal epithelium. Such findings prompt speculation on whether such mutations exist in the eutopic endometrium – the likely tissue of origin of endometriosis. In the current study we investigated the presence of somatic driver mutations in histologically normal endometrium from women lacking evidence of gynecologic malignancy or endometrial hyperplasia. Twenty-five women who underwent hysterectomies and 85 women who underwent endometrial biopsies were included in this study. Formalin-fixed, paraffin-embedded tissue specimens were analyzed by means of targeted sequencing followed by orthogonal validation with droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) was also performed as surrogates for inactivating mutations in the respective genes. Overall, we observed somatic driver-like events in over 50% of histologically normal endometrial samples analyzed, which included hotspot mutations in KRAS, PIK3CA, and FGFR2 as well as PTEN-loss by IHC. Analysis of anterior and posterior samplings collected from women who underwent hysterectomies is consistent with the presence of somatic driver mutations within clonal pockets spread throughout the uterus. The prevalence of such oncogenic mutations also increased with age (OR: 1.05 (95% CI: 1.00 – 1.10), p = 0.035). These findings have implications on our understanding of aging and so-called “normal tissues”, thereby necessitating caution in the utilization of mutation-based early detection tools for endometrial or other cancers.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

Oncogenic Mutations in Histologically Normal Endometrium: The New Normal?

Lac

Nazeran

Tessier‐Cloutier

et al. 2019

Preprint

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“…19 Recently, Suda et al sequenced ovarian endometriotic and normal uterine endometrial epithelium samples obtained from subjects with benign gynecological disease. 20 They also identified somatic mutations in cancer-associated genes such as KRAS and PIK3CA in histologically normal endometrial glands. Therefore, we should carefully assess the subjects with mutations in these genes.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study showed that 10 of 39 infiltrating endometriosis had somatic mutations in genes associated with endometrial cancers such as ARID1A , PIK3CA , KRAS , and PPP2R1A , suggesting that somatic mutations in these genes are involved in endometriosis, a benign disease with clonal proliferation of endometrial cells . Recently, Suda et al sequenced ovarian endometriotic and normal uterine endometrial epithelium samples obtained from subjects with benign gynecological disease . They also identified somatic mutations in cancer‐associated genes such as KRAS and PIK3CA in histologically normal endometrial glands.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of liquid‐based genetic diagnosis of endometrial cancer

et al. 2018

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Although liquid‐based cytology (LBC) has increased the sensitivity of cytological diagnosis of endometrial cancer (EC) compared with conventional smear cytology, the sensitivity of LBC for the detection of EC is between 70% and 96% and remains unsatisfactory. In the present study, we compared the efficacy of LBC with liquid‐based genetic diagnosis (LBGDx) by amplicon sequencing of five genes including PTEN,PIK3CA,CTNNB1,KRAS, and TP53 in 48 LBC subjects who underwent endometrial screening. Consequently, LBC classified 15 samples as “positive or suspicious for malignancy” and the 15 were later confirmed as EC. However, LBC failed to identify five cases who were diagnosed as EC by additional transvaginal ultrasound and endometrial curettage, indicating that the sensitivity of cytology alone was 75% (15/20). LBGDx identified 11 pathogenic PTEN variants in 10 subjects, six PIK3CA variants in nine, three CTNNB1 variants in five, two KRAS variants in four, and three TP53 variants in three. Collectively, at least one pathogenic variant was identified in 19 subjects, which included 17 EC (15 endometrioid carcinoma and 2 endometrial carcinosarcomas), and one cervical adenocarcinoma. However, LBGDx did not identify any pathogenic mutations in three of the 20 EC, indicating that the sensitivity of LBGDx alone was 85% (17/20). Although five EC were negative for malignancy by LBC and three were negative for pathogenic mutations by LBGDx, the combination of LBC and LBGDx would successfully diagnose all 20 EC. These data suggested that LBGDx is a useful strategy to improve the sensitivity of screening of EC by LBC.

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“…Using the same Pax8-rtTA Tre-Cre model but with Confetti mice (Gt(ROSA)26Sor tm1(CAG-Brainbow2.1)Cle /J; Jax Stock No 013731) instead of Ai9 reporter mice, we have observed clonal expansion of cells labeling both glands and luminal epithelium by 90 days after Cre induction (Figure 3). Recent study has reported clonal expansion of normal endometrial epithelial cells with cancer-associated mutations (Suda et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

PAX8 expressing epithelial cells are a cancer-prone source of clonal cyclical regeneration of endometrial epithelium

Micheli

Bidarimath

et al. 2019

Preprint

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Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells. However, their location remains debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported this tissue can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin. Here we show that cells expressing transcription factor PAX8 are the main contributor to the homeostatic regeneration of endometrial epithelium. In the uterus, based on a single-cell transcriptome and immunostaining analyses, PAX8 expression is limited to the endometrial epithelium. According to lineage tracing, PAX8 positive (PAX8+) epithelial cells are responsible for long-term maintenance of the epithelium. Furthermore, multicolor tracing shows that individual glands are formed by clonal expansion of cells labeling both glandular and luminal epithelial components. Inactivation of tumor suppressor genes Trp53 and Rb1 in PAX8+ cells but not FOXJ1+ cells leads to formation of neoplasms with features of serous endometrial carcinoma, the most aggressive type of human endometrial malignancy. Taken together, our results show that a progeny of single PAX8+ cells represent the main source of cyclical regeneration of the endometrial epithelium.They also provide direct experimental genetic evidence for the key roles of the P53 and RB pathways in the pathogenesis of serous endometrial carcinoma, and suggest that PAX8+ cells represent the cell-of-origin of this neoplasm.

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Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium

Cited by 342 publications

References 64 publications

Oncogenic Mutations in Histologically Normal Endometrium: The New Normal?

Oncogenic Mutations in Histologically Normal Endometrium: The New Normal?

Efficacy of liquid‐based genetic diagnosis of endometrial cancer

PAX8 expressing epithelial cells are a cancer-prone source of clonal cyclical regeneration of endometrial epithelium

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