【摘要】：背景:神經(jīng)母細(xì)胞瘤(Neuroblastoma,NB)是嬰幼兒最常見(jiàn)的惡性腫瘤,可發(fā)生在交感神經(jīng)系統(tǒng)的任何部位,預(yù)后極差,且容易遺留慢性健康問(wèn)題,大大降低患者的生活質(zhì)量。NB的病因及發(fā)展過(guò)程極其復(fù)雜,具體的發(fā)病機(jī)制至今未明,因而缺乏有效的預(yù)防和治療手段。既往的5個(gè)主要在歐裔人群中開(kāi)展的全基因組關(guān)聯(lián)研究(Genome-Wide Association Study,GWAS)發(fā)現(xiàn) CASC15、BARD1、LMO1、DUSP12、DDX4、IL31RA、HSD17B12、LIN28B 和 HACE1 基因的 23個(gè)單核苷酸多態(tài)性(Single Nucleotide Polymorphism,SNP)與NB易感性和預(yù)后相關(guān),但亞洲范圍內(nèi)的相關(guān)研究尚未見(jiàn)報(bào)道。目的:通過(guò)對(duì)NB患者及健康人的23個(gè)SNP基因型差異進(jìn)行分析,了解遺傳變異與NB易感性、預(yù)后的相關(guān)性,為形成針對(duì)中國(guó)漢族人群NB的新型靶向診療方案提供理論依據(jù)。方法:采集NB患者的血液、石蠟病例標(biāo)本、健康人的血液標(biāo)本及相關(guān)人口統(tǒng)計(jì)學(xué)及臨床因素信息,提取DNA以實(shí)時(shí)熒光定量PCR(Real-time Quantitative PCR)的方法觀察23個(gè)SNP的基因型分布,以雙側(cè)卡方檢驗(yàn)和Logistic回歸分析了解樣本的流行病學(xué)特征及基因型的分布差異,并根據(jù)年齡及性別因素矯正。收集隨訪信息,根據(jù)患者的人口統(tǒng)計(jì)學(xué)特征、臨床特征和SNP基因型進(jìn)行Kaplan-Meier法生存分析Log-Rank檢驗(yàn)、單因素及多因素COX比例風(fēng)險(xiǎn)模型并根據(jù)流行病學(xué)特征進(jìn)行矯正及分層以探究上述因素與NB患者預(yù)后的相關(guān)性。結(jié)果:1.CASC15 基因的 SNPrs6939340、rs4712653、rs9295536,BARD1 基因的SNPrs7585356、rs6435862、rs3768716,HSD17B12 基因的 SNPrs11037575,LIN28B 基因的 SNPrs221634、rs221634,LMO1 基因 SNPrs110419 與中國(guó)漢族人群NB易感性顯著相關(guān);DDX4基因的SNPrs2619046與NB發(fā)病風(fēng)險(xiǎn)呈邊緣顯著性相關(guān);同一個(gè)基因的多個(gè)SNP的組合效應(yīng)均與NB發(fā)病風(fēng)險(xiǎn)顯著或邊緣性顯著相關(guān)。2.年齡大于18個(gè)月、臨床晚期(Ⅲ-Ⅳ期)、原發(fā)腫瘤部位為后腹膜區(qū)域、腎上腺區(qū)域、其他區(qū)域、腫瘤中低-低分化、腫瘤轉(zhuǎn)移、復(fù)發(fā)是影響NB患者預(yù)后的危險(xiǎn)因素;其中,臨床分期、腫瘤分化程度、是否復(fù)發(fā)、年齡為獨(dú)立預(yù)后相關(guān)因素。HSD17B12基因的SNP rs11037575CT/TT基因型與野生型純合子CC基因型相比可顯著增加NB患者的死亡風(fēng)險(xiǎn)(單因素COX比例風(fēng)險(xiǎn)模型);LMO1基因的SNP rs204938 AG/GG基因型與野生型純合子AA基因型相比可顯著降低NB患者的死亡風(fēng)險(xiǎn)(多因素COX比例風(fēng)險(xiǎn)模型;向前的似然性分析);DDX4基因的SNPrs2619046GA/AA基因型與野生型純合子GG基因型相比可顯著降低NB患者的死亡風(fēng)險(xiǎn)(多因素COX比例風(fēng)險(xiǎn)模型)。結(jié)論:1.遺傳變異及其組合效應(yīng)與NB易感性相關(guān)。2.遺傳變異及部分人口統(tǒng)計(jì)學(xué)、臨床因素與NB預(yù)后相關(guān)。3.本研究首次在中國(guó)漢族人群中證實(shí)并探討了 GWAS發(fā)現(xiàn)的23個(gè)陽(yáng)性SNP與NB易感性、預(yù)后的關(guān)系。下一步工作需多中心、大樣本的前瞻性研究予以驗(yàn)證。
[Abstract]:Background: neuroblastoma (Neuroblastoma,NB) is the most common malignant tumor in infants and young children. It can occur anywhere in the sympathetic nervous system. The etiology and development process of NB is very complicated, and the specific pathogenesis is still unknown, so it lacks effective prevention and treatment. Five previous genomic association studies (Genome-Wide Association Study,GWAS), mainly in European populations, found 23 single nucleotide polymorphisms (SNPs) of CASC15,BARD1,LMO1,DUSP12,DDX4,IL31RA,HSD17B12,LIN28B and HACE1 genes SNP) is associated with susceptibility and prognosis of NB, but studies in Asia have not been reported. Objective: to study the relationship between genetic variation and susceptibility and prognosis of NB by analyzing 23 SNP genotypes in patients with NB and healthy people so as to provide theoretical basis for the formation of a new targeted diagnosis and treatment scheme for NB in Chinese Han population. Methods: the blood samples of NB patients, paraffin wax cases, healthy people's blood samples and related demographic and clinical factors were collected, and DNA was extracted to observe the distribution of 23 SNP genotypes by real-time fluorescence quantitative PCR (Real-time Quantitative PCR). The epidemiological characteristics and genotype distribution of the samples were analyzed by bilateral chi-square test and Logistic regression analysis, and corrected according to age and sex. According to the demographic characteristics, clinical features and SNP genotypes of the patients, Kaplan-Meier survival analysis Log-Rank test was performed. Univariate and multivariate COX proportional risk models were corrected and stratified according to epidemiological characteristics to explore the correlation between these factors and the prognosis of NB patients. Results: the SNPrs221634,rs221634,LMO1 SNPrs110419 of SNPrs6939340,rs4712653,rs9295536,BARD1 gene, SNPrs7585356,rs6435862,rs3768716,HSD17B12 gene and SNPrs11037575,LIN28B gene of 1.CASC15 gene was significantly correlated with NB susceptibility in Chinese Han population. The SNPrs2619046 of DDX4 gene was significantly correlated with the risk of NB, and the combination effect of multiple SNP of the same gene was significantly correlated with the risk of NB. 2. Age > 18 months, clinical advanced stage (stage 鈪，

本文編號(hào)：2407914