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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 鄭永銘(Yung-Ming Jeng) | |
dc.contributor.author | Wan-Ru Lee | en |
dc.contributor.author | 李宛儒 | zh_TW |
dc.date.accessioned | 2021-06-17T07:00:54Z | - |
dc.date.available | 2019-08-27 | |
dc.date.copyright | 2019-08-27 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-01 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/72559 | - |
dc.description.abstract | 子宮肉瘤佔所有子宮惡性腫瘤的3%,常見各種特異性融合基因為其特徵,尤其是子宮內膜間質的腫瘤。Growth Regulation by Estrogen in Breast cancer 1 (GREB1) gene 是經由雌激素受體調節的基因,被認為在荷爾蒙相關性組織和癌症中扮演重要角色。Nuclear Receptor Coactivator 2 (NCOA2) gene作為荷爾蒙核受體的共同活化因子,經由後者之結合其反應片段以調節目標基因。它常被發現參與基因轉位與基因融合而與許多癌症相關。我們在病理學鏡檢下發現數個子宮間質肉瘤特徵相似,並藉由次世代定序發現4個有GREB1基因轉位重組的現象,包括GREB1-NCOA2及新穎的GREB1-NR4A3,GREB1-SS18和GREB1-NCOA1轉位重組,此皆經由反轉錄連鎖聚合酶反應和/或螢光原位雜合技術驗證。加上之前報導的病例,GREB1基因重組腫瘤與ESR11基因重組腫瘤相比,與老年婦女高度相關(P = 0.001),且有絲分裂活性更高。藉由功能性實驗,我們發現GREB1-NCOA2融合基因轉錄活性明顯的升高,因此,可能在抑制分化和促進生長扮演重要角色。 | zh_TW |
dc.description.abstract | Uterine sarcomas account for 3% of all uterine malignancies. Some uterine sarcomas, particularly endometrial stromal tumors, contain a variety of specific fusion genes. Growth Regulation by Estrogen in Breast cancer 1(GREB1) is the estrogen receptor-regulated gene. It is thought to play important roles in hormone-responsive tissues and cancers. Nuclear Receptor Coactivator 2(NCOA2) functions as transcriptional coactivators for nuclear hormone receptors, which regulate their target genes upon binding of cognate response elements. NCOA2 has been found to be involved in translocations that result in fusions with other genes in various cancers. By pathologic and by FISH screening, we identified 4 pathologically similar uterine sarcomas harboring rearranged GREB1, which were later found by RNA sequencing to contain GREB1-NCOA2 and novel GREB1-NR4A3, GREB1-SS18, and GREB1-NCOA1 fusions, respectively. All were validated by RT-PCR and/or FISH. Combined with previously reported cases, compared to ESR1-rearranged tumors, GREB1-rearranged tumors involved significantly older women (P=0.001), and tended to be larger and more mitotically active than ESR1-rearranged uterine tumors resembling ovarian sex cord tumor, a tumor entity showing overlapping features with GREB1-rearragned sarcoma. By functional study, we also identified that GREB1-NCOA2 fusion gene dramatically increased the transcriptional activity, and possibly played important roles in inhibiting differentiation and promoting proliferation of sex hormone-responsive cells. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T07:00:54Z (GMT). No. of bitstreams: 1 ntu-108-R06444003-1.pdf: 14853702 bytes, checksum: ead063707d80bcd36006b361ba8faef1 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | Contents
中文摘要 I Abstract II 1. Introduction 1 1.1. Uterine Sarcoma 1 1.2. Histopathology of uterine sarcoma excluding carcinosarcoma 3 1.3. Genetic fusions in uterine sarcoma 5 1.4. ESR1 6 1.5. GREB1 7 1.6. NCOA2/3 11 1.7. Aim of this study 12 2. Materials and Methods 14 2.1. Cell culture and E2 treatment 13 2.2. Western blot 14 2.3. Luciferase reporter assay 16 2.4. pM1/2/3 reporter assay 16 2.5. Immunohistochemistry 17 2.6. RNA Sequencing and Data Analysis 18 2.7. Validation of Fusion Transcripts by Reverse Transcription PCR 19 2.8. Fluorescence In Situ Hybridization 20 3. Results 22 3.1. Karyotyp of the Index Case 22 3.2. Detection of GREB1-NCOA2 Fusion in Case G1 22 3.3. FISH Screening for Cases with GREB1 or ESR1 Rearrangement 22 3.4. Detection of Fusion Partners in Cases G2, G3 and G4 23 3.5. Gene Expression Profiling and Clustering Analysis 23 3.6. Clinical Features of the Study Cases 24 3.7. Pathologic Features of the Study Cases 25 3.8. Immunohistochemistry 27 3.9. Forced Expression of GREB1-NCOA2 fusion protein in MCF-7 cells 28 3.10. GREB1-NCOA2 Enhanced Transcriptional Activity 29 4. Discussion 30 4.1. Clinicopathologic characterization of a novel uterine sarcoma type harboring GREB1 fusions 32 4.2. We argue that GREB1-rearranged sarcomas are distinct from ESR1-rearranged UTROSCT in terms of the extent of sex cord differentiation and clinical features 34 4.3. The GREB1 gene probably provides its active promoter in the sex hormone-responsive tumor cells to drive the expression of the 3’ partners/(co)activators 34 4.4. The differences between GREB1-rearranged and ESR1-rearranged tumors may also have therapeutic relevance in terms of potential differential response to anti-hormone therapies 36 4.5. Enhanced Transcriptional Activity of GREB1-NCOA2 was not observed in T-HESCs 37 4.6. Conclusions …………………………………………………………………37 5. Figures and Tables 39 6. Supplementary Figures 58 7. References 61 | |
dc.language.iso | en | |
dc.title | 帶有 GREB1、ESR1 以及 NCOA2/3 融合基因之婦科肉瘤之病理與功能性研究 | zh_TW |
dc.title | Pathologic and Functional Study of Gynecologic Sarcomas Harboring GREB1, ESR1, and NCOA2/3 Gene Fusions | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 李仁傑(Jen-Chieh Lee) | |
dc.contributor.oralexamcommittee | 郭冠廷(KUAN-TING KUO),魏凌鴻(Lin-Hung Wei) | |
dc.subject.keyword | 子宮肉瘤,融合基因,GREB1,NCOA2, | zh_TW |
dc.subject.keyword | uterine sarcoma,fusion gene,GREB1,NCOA2, | en |
dc.relation.page | 68 | |
dc.identifier.doi | 10.6342/NTU201902376 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-08-02 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 病理學研究所 | zh_TW |
顯示於系所單位: | 病理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-108-1.pdf 目前未授權公開取用 | 14.51 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。