本文選題：乳腺癌 + 循環(huán)腫瘤細(xì)胞��； 參考：《北京協(xié)和醫(yī)學(xué)院》2017年碩士論文

【摘要】：目的:既往大量研究表明循環(huán)腫瘤細(xì)胞(circulating tumor cells,CTCs)計(jì)數(shù)是轉(zhuǎn)移性乳腺癌預(yù)后因子,但循環(huán)腫瘤細(xì)胞的異質(zhì)性,如上皮間質(zhì)轉(zhuǎn)化可能會(huì)影響其臨床應(yīng)用價(jià)值。乳腺癌治療方案的制定依賴于分子分型的指導(dǎo),由于在侵襲和轉(zhuǎn)移的過程中,腫瘤分子分型可能發(fā)生了一定程度的改變,而有時(shí)往往無法直接獲得轉(zhuǎn)移灶的病理組織,應(yīng)用液態(tài)活檢技術(shù)進(jìn)行CTCs的雌/孕激素受體(ER/PR)檢測(cè)可以實(shí)現(xiàn)對(duì)ER/PR狀態(tài)的實(shí)時(shí)動(dòng)態(tài)監(jiān)測(cè)。本研究旨在探究基于上皮間質(zhì)轉(zhuǎn)化學(xué)說的CTCs分型與乳腺癌ER/PR狀態(tài)的關(guān)系,探索從上皮間質(zhì)轉(zhuǎn)化和CTCs的ER/PR狀態(tài)兩方面兼顧C(jī)TCs異質(zhì)性的簡便易行的檢測(cè)方法。方法:該研究納入28名轉(zhuǎn)移性乳腺癌患者,應(yīng)用CanpatrolTM二代CTC檢測(cè)技術(shù)進(jìn)行外周血CTCs檢測(cè),采用多重RNA原位雜交的方法對(duì)富集的CTCs進(jìn)行特異性基因核酸定位,將CTCs分為上皮型、間質(zhì)型、混合型三種亞型。同時(shí),通過與內(nèi)參基因的熒光信號(hào)強(qiáng)度對(duì)比將每個(gè)CTC的ER/PR狀態(tài)分為高表達(dá)、中表達(dá)、低表達(dá)、無表達(dá)四種狀態(tài)。結(jié)果:原發(fā)灶ER/PR狀態(tài)不同,患者外周血中檢測(cè)到CTCs亞型由上皮型至間質(zhì)型的分布差異有統(tǒng)計(jì)學(xué)意義(Z=-3.569,P0.001);原發(fā)灶ER/PR陽性的患者,其上皮型CTCs所占的比例(41.7%)高于混合型(27.4%)和間質(zhì)型CTCs(30.9%);原發(fā)灶ER/PR陰性患者,間質(zhì)型CTCs所占的比例(43.1%)高于上皮型(30.5%)和混合型CTCs(26.4%)。此外,原發(fā)灶ER/PR狀態(tài)不同,轉(zhuǎn)移后外周血CTCs的ER/PR狀態(tài)由高表達(dá)至低表達(dá)的變化趨勢(shì)也有明顯差異(Z=-3.524,P0.001);原發(fā)灶ER/PR陽性的患者,其CTCs的ER/PR狀態(tài)高表達(dá)所占的比例(5.8%)高于原發(fā)灶ER/PR陰性的患者(3.5%);原發(fā)灶ER/PR陰性的患者,其CTCs的ER/PR狀態(tài)無表達(dá)所占的比例(35.0%)高于原發(fā)灶ER/PR陽性的患者(23.7%)。同時(shí),不同CTCs亞型的ER/PR狀態(tài)變化趨勢(shì)不同(Z=6.405,P=0.041);上皮型CTCs中ER/PR狀態(tài)高表達(dá)所占的比例(8.3%)高于混合型(2.1%)和間質(zhì)型CTCs(3.2%)。結(jié)論:外周血CTCs亞型由上皮型至間質(zhì)型的分布差異與原發(fā)灶ER/PR狀態(tài)有關(guān),CTCs的ER/PR狀態(tài)由高表達(dá)至低表達(dá)的變化趨勢(shì)也隨著原發(fā)灶ER/PR狀態(tài)不同而變化。通過實(shí)時(shí)監(jiān)測(cè)不同亞型CTCs的ER/PR狀態(tài),可以為臨床提供簡便易行的CTCs檢測(cè)方法用于指導(dǎo)晚期乳腺癌患者的內(nèi)分泌治療方案的選擇。目的:既往研究表明晚期乳腺癌的侵襲和轉(zhuǎn)移與上皮間質(zhì)轉(zhuǎn)化的過程相關(guān)。然而對(duì)于早期乳腺癌而言,基于上皮間質(zhì)轉(zhuǎn)化學(xué)說的循環(huán)腫瘤細(xì)胞(circulating tumor cells,CTCs)分型與其臨床病理特征的關(guān)系仍不清楚。本研究旨在探究基于上皮間質(zhì)轉(zhuǎn)化學(xué)說的CTCs分型與早期乳腺癌的臨床病理特征間的關(guān)系,以期為基于上皮間質(zhì)轉(zhuǎn)化學(xué)說的循環(huán)腫瘤細(xì)胞分型用于早期乳腺癌的預(yù)后判斷提供參考。方法:本研究共納入150名早期乳腺癌患者,應(yīng)用CanpatrolTM二代CTC檢測(cè)技術(shù)進(jìn)行外周血CTCs檢測(cè),采用多重RNA原位雜交的方法對(duì)富集的CTCs進(jìn)行特異性基因核酸定位,將CTCs分為上皮型、間質(zhì)型、混合型三種亞型。結(jié)果:通過與患者的臨床病理特征進(jìn)行對(duì)比發(fā)現(xiàn),患者的TNM分期不同,其外周血中檢測(cè)到CTC亞型由上皮型至間質(zhì)型的分布差異有統(tǒng)計(jì)學(xué)意義(Z= 39.723,P0.001),Ⅱ期(41.5%)和Ⅲ期(43.4%)的患者中檢測(cè)出的間質(zhì)型CTCs明顯高于Ⅰ期患者(29.0%)。此外,在不同復(fù)發(fā)風(fēng)險(xiǎn)分組之間,其CTC亞型由上皮型至間質(zhì)型的分布差異也有統(tǒng)計(jì)學(xué)意義(Z=-7.101,P0.001),高危組間質(zhì)型CTCs所占的比例明顯高于中危組(46.2%vs 32.6%)。而原發(fā)灶組織病理Ki 67水平的不同,CTCs各個(gè)亞型分布的變化趨勢(shì)也存在差異(Z=-5.687,P0.001)。結(jié)論:對(duì)于早期乳腺癌患者,不同CTC亞型從上皮型到間質(zhì)型的分布差異與其預(yù)后相關(guān)的臨床病理特征有關(guān),間質(zhì)型CTCs所占比例較高時(shí)可能與一些預(yù)后不良的臨床病理因素具有相似的提示意義,基于上皮間質(zhì)轉(zhuǎn)化學(xué)說的循環(huán)腫瘤細(xì)胞分型可以為早期乳腺癌的預(yù)后判斷提供參考。
[Abstract]:Objective: a large number of previous studies have shown that the circulating tumor cells (CTCs) count is a prognostic factor for metastatic breast cancer, but the heterogeneity of circulating tumor cells, such as epithelial mesenchymal transition, may affect its clinical application. The formulation of breast cancer treatment options depends on the guidance of molecular typing and the invasion and metastasis In the process, the tumor molecular typing may change to a certain extent, and sometimes the pathological tissue of the metastases can not be obtained directly. The detection of the female / progesterone receptor (ER/PR) of CTCs by the liquid biopsy technique can realize the real-time dynamic monitoring of the state of the ER/PR. This study aims to explore the CTCs based on the theory of epithelial mesenchymal transition. The relationship between typing and ER/PR status of breast cancer, and exploring a simple and easy method for detecting CTCs heterogeneity from two aspects of epithelial mesenchymal transition and CTCs's ER/PR status. Methods: This study included 28 metastatic breast cancer patients, using the CanpatrolTM two generation CTC detection technique for peripheral blood CTCs detection and multiple RNA in situ hybridization. The specific gene nucleic acid location of the enriched CTCs was divided into three subtypes of epithelial, interstitial and mixed type. At the same time, the ER/PR state of each CTC was divided into high expression, medium expression, low expression, and no expression of four forms by contrast with the fluorescence intensity of the internal reference gene. Results: the ER/PR state of the primary foci was different and the peripheral blood was detected in the peripheral blood of the patients. The distribution of CTCs subtypes from epithelial to stromal type was statistically significant (Z=-3.569, P0.001), and the proportion of epithelial CTCs in primary ER/PR positive patients (41.7%) was higher than that of mixed type (27.4%) and interstitial CTCs (30.9%); the proportion of interstitial CTCs (43.1%) was higher than that of epithelial type (30.5%) and mixture of primary ER/PR negative patients (30.5%) and mixture. Type CTCs (26.4%). In addition, the ER/PR status of primary foci was different, and the ER/PR state of CTCs in peripheral blood was also significantly different from high expression to low expression (Z=-3.524, P0.001). The proportion of ER/PR state high expression of CTCs in the primary focal ER/PR positive patients (5.8%) was higher than that of the primary ER/PR negative (3.5%); the primary focal ER/PR was ER/PR. Negative patients, the proportion of CTCs ER/PR state non expression (35%) was higher than that of primary ER/PR positive patients (23.7%). Meanwhile, the change trend of ER/PR status in different CTCs subtypes was different (Z=6.405, P=0.041); the proportion of high expression of ER/PR in epithelial CTCs (8.3%) was higher than that of mixed type (2.1%) and interstitial CTCs (3.2%). Conclusion: peripheral blood (3.2%). The distribution of the blood CTCs subtypes from the epithelial type to the interstitial type is related to the ER/PR state of the primary focus. The trend of the ER/PR state from high expression to low expression of CTCs varies with the ER/PR state of the primary focus. By real-time monitoring of the ER/PR state of the different subtypes of CTCs, the simple and convenient CTCs detection method can be used for guidance in clinical practice. Endocrine therapy options for advanced breast cancer. Objective: Previous studies have shown that the invasion and metastasis of advanced breast cancer are associated with the process of epithelial mesenchymal transition. However, for early breast cancer, the circulating tumor cells (CTCs) classification based on the theory of epithelial mesenchymal transformation and its clinicopathological features The relationship is still unclear. The purpose of this study was to explore the relationship between CTCs typing based on epithelial mesenchymal transition and the clinicopathological features of early breast cancer in order to provide reference for predicting the prognosis of early breast cancer based on the theory of epithelial mesenchymal transition. Square method: This study included 150 early breast cancer patients. The CanpatrolTM two generation CTC detection technique was used to detect the peripheral blood CTCs, and the specific gene nucleic acid location of the enriched CTCs was carried out by multiple RNA in situ hybridization. The CTCs was divided into epithelial, interstitial and mixed subtypes. The results were compared with the clinical characteristics of the patients, and the patients' TNM stages were different. In peripheral blood, the distribution of CTC subtypes from epithelial to stromal type was statistically significant (Z= 39.723, P0.001). The interstitial CTCs detected in patients with stage II (41.5%) and stage III (43.4%) was significantly higher than that in phase I patients (29%). In addition, the distribution of CTC subtypes from epithelial to stromal types was also different between different recurrence risk groups. There were statistical significance (Z=-7.101, P0.001), and the proportion of interstitial CTCs in high-risk group was significantly higher than that in middle risk group (46.2%vs 32.6%). The variation trend of CTCs subtype distribution was also different (Z=-5.687, P0.001) in primary pathological Ki 67 levels (Z=-5.687, P0.001). Conclusion: for early breast cancer patients, different CTC subtypes from epithelial to interstitial type The distribution difference is related to the clinicopathological features related to the prognosis. The high proportion of interstitial CTCs may be of similar suggestive significance to some clinicopathological factors that have poor prognosis. The circulating tumor cell classification based on the theory of epithelial mesenchymal transformation can provide reference for the prognosis of early breast cancer.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R737.9

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本文編號(hào)：1911762