本文選題：肺癌　切入點：癌旁組織　出處：《中國科學技術大學》2016年碩士論文

【摘要】：肺癌作為全世界發(fā)病率最高和致死人數(shù)最多的癌癥,發(fā)病原因包括吸煙、職業(yè)暴露、空氣污染和基因突變等,2015年中國腫瘤登記年報顯示,肺癌仍居中國發(fā)病率的首位。半個多世紀以來全世界在肺癌的手術、放療、化療及靶向治療方面取得了巨大的進展和成績,但由于缺乏有效的早期診斷方法且肺癌患者出現(xiàn)癥狀時多為晚期,因而總的5年存活率不到15%�；蛲蛔冏鳛榉伟┌l(fā)生的誘因之一,突變率隨著環(huán)境污染的加劇而不斷提高,細胞癌變的概率也隨之增加。肺癌的特點之一是具有異質性,對基因突變的分析對于揭示肺癌發(fā)生發(fā)展有重要作用,隨著肺癌測序技術的快速發(fā)展,越來越多的突變基因被發(fā)現(xiàn),其中包括EGFR、KRAS等一些肺癌發(fā)生中重要的驅動突變,為肺癌的早期診斷和靶向治療提供了新的方向。與腫瘤組織一樣,腫瘤的正常對照組織也同樣暴露在煙草等環(huán)境致癌物中,為了研究這些組織基因組在環(huán)境致癌物中發(fā)生的變化,我們從TCGA數(shù)據(jù)庫下載了513例肺腺癌病人的全外顯子數(shù)據(jù),篩選出癌旁特有的基因組異常點并過濾掉體細胞突變,統(tǒng)計突變特征并對病人進行生存分析后繪制病人生存曲線,然后選取癌旁組織突變與病人預后相關的基因進行初步的功能研究。在癌旁組織突變基因中,外顯子突變頻率為0.93/Mb,堿基突變以C：GT：A的置換為主,有29個基因突變率大于3%,其中ZNF511和TMEM184A與預后成正相關,其中ZNF511在513例病人中有16例癌旁發(fā)生突變且該基因存在三種突變情況,突變的結果是蛋白質產(chǎn)物的縮短或延長,癌旁中ZNF511發(fā)生突變與病人的預后是成正相關的。然而目前對于ZNF511基因功能還尚未有研究,因此我們想通過基因的過表達和干擾對ZNF511進行初步的功能研究。因此我們對ZNF511瞬時轉染同時構建慢病毒穩(wěn)轉株,設計并合成了小RNA干擾序列在肺腺癌細胞系A549細胞中進行干擾,初步顯示敲低ZNF511后對細胞增殖能力有一定抑制作用,且可以引起pAKT的下調(diào)�？傊�,本文對肺腺癌中正常的對照組織基因組變異情況進行了系統(tǒng)的分析并對ZNF511基因功能做了初步研究,為肺癌發(fā)生發(fā)展的機理提供了全新的思路。
[Abstract]:Lung cancer has the highest incidence and the highest number of deaths in the world. The causes of lung cancer include smoking, occupational exposure, air pollution and gene mutation, according to the 2015 China Cancer Registry Annual report. Lung cancer still ranks first in China. Over the past half century, the world has made great progress and achievements in surgery, radiotherapy, chemotherapy and targeted treatment of lung cancer. However, due to the lack of effective early diagnosis methods and the late stage of lung cancer, the total 5-year survival rate is less than 15%. Gene mutation is one of the inducements of lung cancer, and the mutation rate increases with the increase of environmental pollution. One of the characteristics of lung cancer is its heterogeneity. The analysis of gene mutation plays an important role in revealing the occurrence and development of lung cancer, and with the rapid development of lung cancer sequencing technology, More and more mutant genes have been found, including some important driving mutations in the carcinogenesis of lung cancer, such as EGFRX KRAS, which provide a new direction for early diagnosis and targeted treatment of lung cancer. The normal control tissue of the tumor was also exposed to environmental carcinogens such as tobacco. In order to study the changes of these tissue genomes in environmental carcinogens, we downloaded the total exon data from 513 patients with lung adenocarcinoma from the TCGA database. Screening out specific genomic anomalies beside cancer, filtering out somatic mutations, counting mutation characteristics, and making survival analysis of patients and drawing patient survival curves. The mutation frequency of exon in paracancerous tissue mutation was 0.93Mb, and the base mutation was mainly C:GT:A replacement. The mutation rate of 29 genes was more than 3, in which ZNF511 and TMEM184A were positively correlated with prognosis. ZNF511 mutation occurred in 16 out of 513 patients and there were three mutations in the gene. The result of mutation was the shortening or prolongation of protein products. There is a positive correlation between the mutation of ZNF511 and the prognosis of patients with cancer. However, the function of ZNF511 gene has not been studied yet. Therefore, we want to study the function of ZNF511 by gene overexpression and interference. Therefore, we constructed a stable lentivirus strain by transient transfection of ZNF511 and designed and synthesized a small RNA interference sequence for interference in lung adenocarcinoma cell line A549. Preliminary results show that ZNF511 knockout has a certain inhibitory effect on cell proliferation, and can cause down-regulation of pAKT. In this paper, the genomic variation of normal control tissues in lung adenocarcinoma was systematically analyzed, and the function of ZNF511 gene was preliminarily studied, which provided a new idea for the pathogenesis of lung cancer.
【學位授予單位】：中國科學技術大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R734.2
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本文編號：1668206