遗传变异与神经母细胞瘤易感性、预后关系的分子流行病学研究

发布时间：2019-01-12 15:07

【摘要】：背景:神经母细胞瘤(Neuroblastoma,NB)是婴幼儿最常见的恶性肿瘤,可发生在交感神经系统的任何部位,预后极差,且容易遗留慢性健康问题,大大降低患者的生活质量。NB的病因及发展过程极其复杂,具体的发病机制至今未明,因而缺乏有效的预防和治疗手段。既往的5个主要在欧裔人群中开展的全基因组关联研究(Genome-Wide Association Study,GWAS)发现 CASC15、BARD1、LMO1、DUSP12、DDX4、IL31RA、HSD17B12、LIN28B 和 HACE1 基因的 23个单核苷酸多态性(Single Nucleotide Polymorphism,SNP)与NB易感性和预后相关,但亚洲范围内的相关研究尚未见报道。目的:通过对NB患者及健康人的23个SNP基因型差异进行分析,了解遗传变异与NB易感性、预后的相关性,为形成针对中国汉族人群NB的新型靶向诊疗方案提供理论依据。方法:采集NB患者的血液、石蜡病例标本、健康人的血液标本及相关人口统计学及临床因素信息,提取DNA以实时荧光定量PCR(Real-time Quantitative PCR)的方法观察23个SNP的基因型分布,以双侧卡方检验和Logistic回归分析了解样本的流行病学特征及基因型的分布差异,并根据年龄及性别因素矫正。收集随访信息,根据患者的人口统计学特征、临床特征和SNP基因型进行Kaplan-Meier法生存分析Log-Rank检验、单因素及多因素COX比例风险模型并根据流行病学特征进行矫正及分层以探究上述因素与NB患者预后的相关性。结果: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 与中国汉族人群NB易感性显著相关;DDX4基因的SNPrs2619046与NB发病风险呈边缘显著性相关;同一个基因的多个SNP的组合效应均与NB发病风险显著或边缘性显著相关。2.年龄大于18个月、临床晚期(Ⅲ-Ⅳ期)、原发肿瘤部位为后腹膜区域、肾上腺区域、其他区域、肿瘤中低-低分化、肿瘤转移、复发是影响NB患者预后的危险因素;其中,临床分期、肿瘤分化程度、是否复发、年龄为独立预后相关因素。HSD17B12基因的SNP rs11037575CT/TT基因型与野生型纯合子CC基因型相比可显著增加NB患者的死亡风险(单因素COX比例风险模型);LMO1基因的SNP rs204938 AG/GG基因型与野生型纯合子AA基因型相比可显著降低NB患者的死亡风险(多因素COX比例风险模型;向前的似然性分析);DDX4基因的SNPrs2619046GA/AA基因型与野生型纯合子GG基因型相比可显著降低NB患者的死亡风险(多因素COX比例风险模型)。结论:1.遗传变异及其组合效应与NB易感性相关。2.遗传变异及部分人口统计学、临床因素与NB预后相关。3.本研究首次在中国汉族人群中证实并探讨了 GWAS发现的23个阳性SNP与NB易感性、预后的关系。下一步工作需多中心、大样本的前瞻性研究予以验证。
[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，

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