本文選題：肝細(xì)胞癌　+ PcG家族　；參考：《吉林大學(xué)》2017年碩士論文

【摘要】：肝細(xì)胞癌(HCC)是最常見(jiàn)的肝臟惡性腫瘤之一,根據(jù)調(diào)查發(fā)現(xiàn),HCC的發(fā)病率在所有癌癥中排名第五位。有研究顯示,在2012年全球約有782500例新發(fā)HCC病例,死亡病例約745500例,其中中國(guó)約占全球總數(shù)的50%。導(dǎo)致HCC發(fā)生的機(jī)制十分復(fù)雜,已有的研究認(rèn)為乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)的慢性感染和隨后肝部的再生循環(huán)損傷為HCC的主要病因。同時(shí),遺傳和表觀遺傳因素在HCC的發(fā)生、發(fā)展中亦發(fā)揮重要的作用。在HCC發(fā)病機(jī)制研究中,學(xué)者們發(fā)現(xiàn)組蛋白甲基化,尤其是H3K27me3可以通過(guò)抑制相關(guān)抑癌基因的功能,促進(jìn)HCC的發(fā)生和進(jìn)展。同時(shí),PcG家族作為H3K27me3的主要催化酶,在HCC的表觀遺傳學(xué)中亦積累了大量的研究工作�？偨Y(jié)發(fā)現(xiàn):⑴PcG家族不僅可以通過(guò)H3K27依賴途徑發(fā)揮促癌作用,還可以通過(guò)非H3K27依賴途徑促進(jìn)HCC的發(fā)生,但機(jī)制尚不明確。⑵PcG家族基因多態(tài)性和突變與腫瘤發(fā)生之間存在顯著關(guān)聯(lián),但目前與HCC易感性之間的關(guān)聯(lián)尚鮮見(jiàn)報(bào)道,有待于進(jìn)一步研究與分析。目的:研究分析PcG家族基因的多態(tài)性與HCC的遺傳相關(guān)性。方法:本次研究納入HCC患者175例,健康對(duì)照者231例,所有研究對(duì)象均為中國(guó)漢族人。經(jīng)HCC患者組和正常對(duì)照組兩組研究對(duì)象知情同意后,各抽取外周靜脈血5ml,采用血液基因組提取試劑盒(離心柱型)提取406例研究對(duì)象的全基因組DNA。本研究中共選擇PcG家族3個(gè)基因(EZH2,CBX8和EED)的9個(gè)多態(tài)性位點(diǎn),分別為:rs2302427,rs3757441,rs41277434,rs4889891,rs62000363,rs9905914,rs1391221,rs7952481和rs974144。應(yīng)用MALDI-TOF-MS技術(shù)來(lái)檢測(cè)本研究所選擇的3個(gè)基因9個(gè)位點(diǎn)的基因型。使用Excel 2007軟件錄入所有數(shù)據(jù)并進(jìn)行整理,采用SPSS 17.0軟件對(duì)研究對(duì)象的數(shù)據(jù)進(jìn)行統(tǒng)計(jì)分析,用SNPStats在線數(shù)據(jù)處理程序?qū)蛐瓦M(jìn)行分析。用均數(shù)±標(biāo)準(zhǔn)差(`X±s)來(lái)表示統(tǒng)計(jì)描述,用中位數(shù)(四分位數(shù)間距)表示臨床指標(biāo)數(shù)據(jù),用百分比表示計(jì)數(shù)資料;用χ2檢驗(yàn)檢測(cè)SNPs的等位基因頻率;對(duì)于每個(gè)SNP,采用Hardy-Weinberg檢驗(yàn)進(jìn)行檢測(cè);用χ2檢驗(yàn)來(lái)分析照組與病例組之間的SNP基因型分布、等位基因頻率;使用非參數(shù)檢驗(yàn)或單因素方差分析來(lái)評(píng)價(jià)SNP與臨床指標(biāo)參數(shù)的關(guān)聯(lián)性.結(jié)果:⑴本次研究共納入HCC患者175例,正常對(duì)照者231例。病例組中包含男性147例,女性26例,男女性別比例為5.25:1;對(duì)照組中包含男性157例,女性68例,男女性別比例為2.33:1。病例組和對(duì)照組的平均年齡分別為56.83±13.37歲和55.21±12.61歲。年齡和性別在兩組之間的差異均沒(méi)有統(tǒng)計(jì)學(xué)意義(All P0.05)。⑵EZH2基因3個(gè)位點(diǎn)和EED基因3個(gè)位點(diǎn)的基因型分布均符合Hardy-Weinberg平衡定律。⑶EZH2基因除了rs41277434位點(diǎn)的基因型分布在病例組和對(duì)照組之間沒(méi)有差異之外,其他兩個(gè)位點(diǎn)(rs2302427和rs3757441)的差異都具有統(tǒng)計(jì)學(xué)意義(P0.05);EED基因rs4889891,rs62000363和rs9905914位點(diǎn)的基因型分布和等位基因頻率在病例組和對(duì)照組之間的差異都沒(méi)有統(tǒng)計(jì)學(xué)意義(P0.05);CBX8基因rs4889891位點(diǎn)的基因型分布和等位基因頻率在病例組和對(duì)照組之間的差異無(wú)統(tǒng)計(jì)學(xué)意義,其余兩個(gè)位點(diǎn),由于其他基因型和等位基因頻率低于1%,不存在統(tǒng)計(jì)學(xué)意義。⑷在四種遺傳模型下,EZH2的三個(gè)位點(diǎn)中,除了rs3757441位點(diǎn)的超顯性模型(P0.05)和rs41277434位點(diǎn)的隱形模型(P0.05)外,其余均與HCC的發(fā)生存在明顯關(guān)聯(lián)(P0.05);EED基因3個(gè)位點(diǎn)和CBX8基因的3個(gè)位點(diǎn)的多態(tài)性分布在病例組與對(duì)照組之間不具有統(tǒng)計(jì)學(xué)差異(All P0.05)。⑸單倍型分析結(jié)果顯示,EZH2基因中單倍型CCA在總樣本中占23.69%,其分布在病例組與對(duì)照組之間顯著不同(OR=2.03;CI,1.29-3.19;P0.05);EED基因的單倍型分析結(jié)果顯示,在總樣本中單倍型的分布在病例組與對(duì)照組之間沒(méi)有顯著不同(P0.05);CBX8基因的單倍型分析結(jié)果顯示,單倍型ATG在總樣本中占42.18%,其分布在病例組與對(duì)照組之間顯著不同(OR=2.44;CI,1.83-3.25;P0.05)。⑹與HCC患者臨床相關(guān)指標(biāo)的數(shù)量性狀分析結(jié)果顯示,3種基因9個(gè)位點(diǎn)中除了EZH2的rs2302427多態(tài)性與AST指標(biāo)具有顯著性差異之外(P0.05),其余位點(diǎn)的多態(tài)性與HCC患者其他臨床指標(biāo)之間的差異不具有統(tǒng)計(jì)學(xué)意義(P0.05)。結(jié)論:1、EZH2基因三個(gè)位點(diǎn)的多態(tài)性與HCC的發(fā)生之間存在顯著關(guān)聯(lián)。⑴攜帶rs2302427 G等位基因和CCA單倍型的個(gè)體具有較高的HCC風(fēng)險(xiǎn),且rs2302427的G等位基因與臨床指標(biāo)AST顯著相關(guān)。⑵rs3757441的等位基因頻率、基因型分布和遺傳模型分析結(jié)果在病例組和對(duì)照組之間存在明顯差異,但rs3757441多態(tài)性與HCC患者的臨床指標(biāo)之間沒(méi)有顯著關(guān)聯(lián)。⑶rs41277434等位基因在病例組與對(duì)照組之間存在顯著差異,且攜帶C等位基因的個(gè)體與攜帶其他等位基因的個(gè)體相比HCC風(fēng)險(xiǎn)降低。2、未發(fā)現(xiàn)EED基因三個(gè)位點(diǎn)rs7952481、rs1391221和rs974144的多態(tài)性與HCC易感性之間存在關(guān)聯(lián)。3、CBX8基因的rs62000363,rs9905914位點(diǎn)的基因型和等位基因頻率低于1%,無(wú)法進(jìn)行統(tǒng)計(jì)學(xué)分析;rs4889891位點(diǎn)的基因型分布和等位基因頻率在病例組和對(duì)照組之間的差異無(wú)統(tǒng)計(jì)學(xué)意義,與之前的研究結(jié)果矛盾,需進(jìn)行進(jìn)一步的研究與驗(yàn)證。
[Abstract]:Hepatocellular carcinoma (HCC) is one of the most common malignant tumor of the liver, according to the survey found that the incidence of HCC in all cancer ranked fifth. Studies have shown that in 2012 there are around 782500 new cases of HCC cases, around 745500 deaths, of which Chinese accounted for the total number of 50%. in mechanism the occurrence of HCC is very complex, according to the studies of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and subsequent regeneration of chronic liver injury is the main cause of the HCC cycle. At the same time, genetic and epigenetic factors in the occurrence of HCC, but also play an important role in the development of research in the pathogenesis of HCC. In the mechanism, the scholars found that histone methylation, especially H3K27me3 can inhibit tumor suppressor gene function, promote the occurrence and development of HCC. At the same time, the PcG family as the main catalytic enzyme H3K27me3, HCC in epigenetics in product Tired of a lot of research work. It was found that the PcG family can not only through the H3K27 dependent pathway to promote cancer, can also occur through non H3K27 dependent pathway to promote HCC, but the mechanism is not clear. The PcG gene polymorphisms and mutations and tumor occurrence between the significant correlation, but correlation between the current and HCC susceptibility was rarely reported, for further research and analysis. Objective: To study correlation of genetic polymorphism analysis of PcG gene family and HCC. Methods: This study included 175 cases of HCC patients and 231 healthy subjects. All the research objects are Chinese by Han people. The group of patients with HCC and normal the control group of two groups of subjects after informed consent, the peripheral venous blood of 5ml were selected, using the blood genomic DNA Extraction Kit (centrifugal column type) extraction of genomic DNA. of 406 subjects in this study were selected family of PcG 3 base Because of (EZH2, CBX8 and EED) of 9 polymorphic loci, respectively: rs2302427, rs3757441, rs41277434, rs4889891, rs62000363, rs9905914, rs1391221, rs7952481 and rs974144. using MALDI-TOF-MS technology to detect the genotype of the selected 3 genes of 9 loci. Excel 2007 software was used to input all the data and finishing on the study of the data were analyzed by SPSS 17 software, the genotypes were analyzed by SNPStats online data processing program. With the mean and standard deviation (`X + s) to represent the statistical description, with the median (four percentile interval) said the clinical data, said the count data were percentage; 2 inspection of SNPs allele frequency; for each SNP, Hardy-Weinberg test was used for detection; 2 test to analyze the SNP genotype between group and case group with chi square distribution, allele frequency; using non parametric The number of correlation test and single factor variance analysis to evaluate the parameters of SNP and clinical index. Results: the present study included 175 HCC patients and 231 normal subjects were included in the case group. 147 cases were male, 26 were female, the gender ratio is 5.25:1; the control group included 157 cases of male and female in 68 cases, the average age of the gender ratio of 2.33:1. and control group were 56.83 + 13.37 and 55.21 + 12.61 years. Age and gender differences between the two groups were not statistically significant (All P0.05). Genotypes of the 3 SNPs of EZH2 gene and EED gene 3 loci were in accordance with the distribution Hardy-Weinberg equilibrium. EZH2 gene rs41277434 locus genotype distribution except that there is no difference between the case group and the control group, the other two loci (rs2302427 and rs3757441) were statistically significant (P0.05); EED gene rs4889891, RS6 Genotype 2000363 and rs9905914 loci and allele frequency distribution differences between the case group and the control group were not statistically significant (P0.05); genotype CBX8 gene rs4889891 locus and allele frequency distribution differences between the case and control groups were not statistically significant, the remaining two loci, because of the other genotype and allele frequencies of less than 1%, there is no statistical significance. In four kinds of genetic models, three loci of EZH2, in addition to overdominance model rs3757441 loci (P0.05) contact model and rs41277434 loci (P0.05), the rest were significantly associated with the occurrence of HCC (P0.05); polymorphism of 3 EED loci and 3 loci of the CBX8 gene has no statistical difference between the case group and the control group (All P0.05). The haplotype analysis showed that haplotype of EZH2 gene in CCA accounted for 23 of the total sample .69%, which is distributed between the case group and the control group were significantly different (OR=2.03; CI, 1.29-3.19; P0.05); EED gene haplotype analysis results show that the distribution of haplotypes in the total sample between the case group and the control group were not significantly different (P0.05); CBX8 gene haplotype analysis results showed that haplotype ATG 42.18% of the total sample, the distribution between case group and control group were significantly different (OR=2.44; CI, 1.83-3.25; P0.05). 6 quantitative traits analysis results in patients with HCC related clinical indexes showed that 3 genes of 9 loci except rs2302427 EZH2 polymorphism and AST index had significant difference (except P0.05), the differences between the remaining polymorphisms and other clinical indicators of HCC patients was not statistically significant (P0.05). Conclusion: 1. There was significant correlation between EZH2 gene polymorphism and three loci of HCC. 1 with rs2302427 G The alleles and CCA haplotype in individuals with higher risk of HCC and rs2302427 were significantly correlated with the G allele of AST rs3757441. The clinical indicators of the allele frequency, genotype distribution and genetic model analysis results between the case group and the control group have obvious difference, but there was no significant association between rs3757441 polymorphism of clinical indicators in patients with HCC. The rs41277434 allele has significant difference between the case group and the control group, and the individuals carrying the C allele compared with other allele HCC reduced the risk of.2, found EED gene three loci rs7952481, there is an association between.3 polymorphism and rs974144 and rs1391221 the susceptibility to HCC, CBX8 gene rs62000363, rs9905914 locus genotype and allele frequencies of less than 1%, can not be analyzed statistically; rs4889891 locus genotype distribution and allele frequency The difference between the case group and the control group was not statistically significant, and it was inconsistent with the previous research results, and further research and verification were needed.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R735.7

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