發(fā)布時(shí)間：2018-03-01 07:06

  本文關(guān)鍵詞： 肝細(xì)胞癌 肝外轉(zhuǎn)移 微陣列比較基因組雜交 拷貝數(shù)變異　出處：《安徽醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：目的肝細(xì)胞癌(hepatocellular carcinoma,HCC)是國(guó)內(nèi)常見(jiàn)的惡性腫瘤,手術(shù)仍是目前HCC的主要根治性治療方法,而術(shù)后肝外轉(zhuǎn)移是患者預(yù)后差的一個(gè)重要因素。但目前對(duì)于具有何種分子特征的HCC易發(fā)生肝外轉(zhuǎn)移仍知之甚少,因此篩選HCC術(shù)后肝外轉(zhuǎn)移相關(guān)分子標(biāo)志具有重要意義。既往研究顯示DNA拷貝數(shù)變異(copy number aberrations,CNAs)與多種腫瘤進(jìn)展和預(yù)后有關(guān),且與HCC術(shù)后肝內(nèi)復(fù)發(fā)相關(guān),但CNAs與HCC術(shù)后遠(yuǎn)處轉(zhuǎn)移的關(guān)系仍不清楚。本研究旨在探討HCC術(shù)后肝外轉(zhuǎn)移相關(guān)的CNAs分子標(biāo)志。方法以66例HCC術(shù)后患者為研究對(duì)象,隨訪首次出現(xiàn)肝外轉(zhuǎn)移的時(shí)間,無(wú)肝外轉(zhuǎn)移生存時(shí)間定義為手術(shù)至出現(xiàn)肝外轉(zhuǎn)移或末次隨訪之時(shí)間間隔。采用高分辨率Agilent 244K微陣列比較基因組雜交(array-based comparative genomic hybridization,a CGH)技術(shù)檢測(cè)HCC組織基因組DNA的CNAs。采用Agilent G2565BA DNA微陣列掃描儀對(duì)雜交芯片進(jìn)行掃描,運(yùn)用Feature Extraction v9.5進(jìn)行數(shù)據(jù)提取與分析。全基因組CNAs與HCC術(shù)后遠(yuǎn)處轉(zhuǎn)移的相關(guān)性分析采用Cox風(fēng)險(xiǎn)比例模型和Log-rank檢驗(yàn),以Kaplan-Meier繪制生存曲線。P0.05為差異有統(tǒng)計(jì)學(xué)意義。統(tǒng)計(jì)學(xué)分析采用Stata 13.0統(tǒng)計(jì)學(xué)軟件包(Stata Corporation,College Station,TX)。結(jié)果1.全組66例HCC樣本的術(shù)后隨訪時(shí)間為1.6~90.5個(gè)月,中位隨訪時(shí)間39.9個(gè)月,總隨訪時(shí)間2633.4人月,隨訪期間共有25例(37.9%)患者出現(xiàn)肝外轉(zhuǎn)移。2.單因素Cox分析顯示,5個(gè)臨床病理學(xué)因素與HCC術(shù)后肝外轉(zhuǎn)移顯著相關(guān)(均P0.05),其中高血壓史、無(wú)完整腫瘤包膜、高TNM分期(Ⅲ期)為危險(xiǎn)因素,而低血小板計(jì)數(shù)(100×109/L)和凝血酶原時(shí)間延長(zhǎng)(12秒)為保護(hù)因素。3.全基因組CNAs與HCC術(shù)后遠(yuǎn)處轉(zhuǎn)移的單因素Cox分析顯示,5個(gè)CNAs片段是肝外轉(zhuǎn)移的顯著相關(guān)因素(均P0.05),其中6p21.32增益、15q11.2增益和20q12-13.13增益是HCC術(shù)后肝外轉(zhuǎn)移的危險(xiǎn)因素;4q12丟失和4q28.1-35.2丟失是轉(zhuǎn)移保護(hù)因素。4.HCC術(shù)后肝外轉(zhuǎn)移相關(guān)因素的多元逐步Cox回歸分析結(jié)果顯示,6p21.32增益、4q28.1-4q35.2缺失、高TNM分期(Ⅲ期)和高血壓史是HCC術(shù)后遠(yuǎn)處轉(zhuǎn)移的獨(dú)立預(yù)后因素(均P0.05),其中6p21.32增益、高TNM分期和高血壓史是轉(zhuǎn)移危險(xiǎn)因素,而4q28.1-4q35.2缺失是轉(zhuǎn)移保護(hù)因素。5.CNAs組合與HCC術(shù)后肝外轉(zhuǎn)移的相關(guān)性:依據(jù)6p21.32增益與4q28.1-35.2丟失狀態(tài)優(yōu)化組合,發(fā)現(xiàn)6p21.32增益、6p21.32無(wú)增益/4q28.1-35.2丟失和6p21.32無(wú)增益/4q28.1-35.2無(wú)丟失3組HCC的術(shù)后無(wú)肝外轉(zhuǎn)移生存差異有統(tǒng)計(jì)學(xué)意義(Log-rank檢驗(yàn),P0.01);相比6p21.32無(wú)增益/4q28.1-35.2無(wú)丟失組,6p21.32無(wú)增益/4q28.1-35.2丟失組的肝外轉(zhuǎn)移風(fēng)險(xiǎn)顯著降低至0.18倍(95%CI=0.06~0.57,P0.01),而6p21.32增益組的肝外轉(zhuǎn)移風(fēng)險(xiǎn)顯著增加至2.91倍(95%CI=1.13~7.46,P0.05)。結(jié)論1.6p21.32增益、15q11.2增益和20q12-13.13增益是HCC術(shù)后肝外轉(zhuǎn)移的危險(xiǎn)因素,而4q12丟失和4q28.1-35.2丟失是轉(zhuǎn)移保護(hù)因素。2.6p21.32增益和4q28.1-35.2丟失是HCC術(shù)后肝外轉(zhuǎn)移的獨(dú)立預(yù)后因素,前者是轉(zhuǎn)移危險(xiǎn)因素,后者是轉(zhuǎn)移保護(hù)因素。3.基于6p21.32增益和4q28.1-35.2丟失2個(gè)獨(dú)立預(yù)后因素的CNAs優(yōu)化組合可在手術(shù)早期對(duì)HCC術(shù)后肝外轉(zhuǎn)移風(fēng)險(xiǎn)作出預(yù)判,從而為臨床治療決策提供依據(jù)。
[Abstract]:Objective hepatocellular carcinoma (hepatocellular, carcinoma, HCC) is a common malignant tumor in China, surgery is still the main HCC radical treatment methods, and postoperative liver metastasis is an important factor of poor prognosis. But for what is the molecular characteristics of HCC susceptible to extrahepatic metastasis remains poorly understood. The screening of HCC postoperative extrahepatic metastasis related molecular markers is important. Previous studies have shown that the copy number variation of DNA (copy number aberrations, CNAs) associated with the progression and prognosis of various tumors, and is associated with intrahepatic recurrence after HCC, but the relationship between CNAs and metastasis after HCC remains unclear. The purpose of this study is to to investigate the HCC postoperative extrahepatic metastasis CNAs molecular marker related. Methods 66 cases of HCC patients were followed up for the first time as the research object, extrahepatic metastasis, extrahepatic metastasis survival time is defined as to the liver surgery. Shift or last follow-up time interval. By using high resolution Agilent 244K microarray comparative genomic hybridization (array-based comparative genomic hybridization, a CGH DNA HCC) in detecting genomic organization technology using CNAs. Agilent G2565BA DNA microarray scanner on hybrid chip scan, using Feature Extraction v9.5 data extraction and analysis of genomic CNAs and correlation analysis. After HCC of distant metastasis with Cox proportional hazard model and Log-rank test, Kaplan-Meier.P0.05 to draw survival curves for significant difference. Statistical analysis using Stata 13 statistical software package (Stata Corporation, College Station, TX). All 66 cases were followed up for 1. HCC sample results after operation for 1.6~90.5 months. After a median follow-up of 39.9 months, the total follow-up time of 2633.4 months follow-up period, a total of 25 cases (37.9%) patients with liver. Shift.2. Cox univariate analysis showed that 5 factors of clinical pathology and HCC postoperative extrahepatic metastasis was significantly correlated (P0.05), the history of hypertension, no intact tumor capsule, high TNM stage (stage III) as a risk factor, and low platelet count (100 x 109/L) and prothrombin time (12 a second) appear as single factors of distant metastasis protective factors of.3. genomic CNAs and HCC after Cox analysis, 5 CNAs fragments were significantly related with extrahepatic metastasis (P0.05), the 6p21.32 gain, 15q11.2 gain and 20q12-13.13 gain are risk factors of HCC postoperative extrahepatic metastasis; 4q12 loss and 4q28.1-35.2 loss multiple factors related to transfer of protective factors of.4.HCC postoperative extrahepatic metastasis by Cox regression analysis showed that the 6p21.32 gain, 4q28.1-4q35.2 loss, high TNM stage (stage III) and history of hypertension is an independent prognostic factor for distant metastasis after HCC (P0.05), of which 6 P21.32 high gain, TNM staging and history of hypertension were the risk factors of metastasis, metastasis and 4q28.1-4q35.2 deletion is a protective factor for.5.CNAs in combination with HCC postoperative extrahepatic metastasis: Based on the 6p21.32 gain and 4q28.1-35.2 lost state optimization, 6p21.32 gain, 6p21.32 no gain without liver loss of /4q28.1-35.2 and 6p21.32 gain /4q28.1-35.2 without loss of 3 HCC the postoperative metastasis survival difference was statistically significant (Log-rank, P0.01); no gain no loss compared to 6p21.32 /4q28.1-35.2 group, 6p21.32 /4q28.1-35.2 group of liver abversion gain loss risk shift significantly reduced to 0.18 times (95%CI=0.06~0.57, P0.01), and the risk of 6p21.32 gain group extrahepatic metastasis significantly increased to 2.91 times (95%CI=1.13~7.46, P0.05). Conclusion 1.6p21.32 gain, 15q11.2 gain and 20q12-13.13 gain are risk factors of HCC postoperative extrahepatic metastasis, and loss of 4q12 and 4q28.1-35. 2 transfer loss is a protective factor for.2.6p21.32 gain and loss of 4q28.1-35.2 were independent prognostic factors of HCC postoperative extrahepatic metastasis, the former is the transfer of risk factors, the latter is the transfer of protective factors.3. optimization can be in operation early on HCC postoperative extrahepatic metastasis risk to predict CNAs 6p21.32 gain and 4q28.1-35.2 lost 2 independent prognostic factors based on, so as to provide the basis for clinical decision making.

【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R735.7

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