NRP1及相关基因的单核苷酸多态性与晚期胃癌一线化疗相关性

发布时间：2018-03-08 07:00

本文选题：晚期胃癌　切入点：SNP　出处：《大连医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：背景和目的胃癌是我国最常见的消化道恶性肿瘤,其发病率和死亡率高居我国恶性肿瘤中第二位。NRP-1是一种重要的Ⅰ型跨膜蛋白,参与肿瘤的发生、发展,它主要通过3条途径参与调节肿瘤的生物学活动:VEGF-VEGFR2通路、PDGF-PDGFR通路、NRP-1-ABL通路。目前发现其涉及的生物学作用包括促进肿瘤的发生、发展,促进肿瘤血管新生,促进肿瘤的迁移、侵袭,参与调节肿瘤对于化疗药物等的敏感性。单核苷酸多态性是第三代遗传标记物,指同一位点的不同等位基因之间仅有个别核苷酸的差异或只有小的插入、缺失等,可以直接影响蛋白质表达和功能,其具有遗传稳定、分布广泛、频率易统计、易分析、适于大规模筛查的优点。目前已有的研究显示,在胃癌的个体差异中,遗传因素起到极大作用。但是目前与胃癌相关的SNP研究仍主要集中在疾病的易感性方面,在晚期胃癌的化疗敏感性方面仍然缺乏相关研究。本研究拟结合目前在晚期胃癌中遇到的问题,结合最新的技术手段,从DNA水平上分析NRP-1及其所参与的通路中部分基因的SNP与晚期胃癌治疗之间的关系,希望能为预测化疗敏感性等提供可能的标志,以达到个体化治疗的目的。材料与方法选取2010年1月至2016年5月于大连医科大学附属第二医院的晚期胃癌化疗患者共82例,取出其病理石蜡标本,使用QIAamp DNA FFPE Tissue Kit试剂盒提取DNA。在NCBI的1000 genome projects的公共SNP数据库中选择目标基因的标签SNP位点,根据所在位置和以往文献进行筛选,采用SNaPshot方法进行测序,检测患者的基因多态性。根据患者的临床病历资料收集患者的临床信息,并通过临床随访和电话随访进一步完善相关信息。使用RECIST标准评价患者化疗疗效。针对各组患者临床资料的差异,使用SPSS 22.0统计软件分析各位点的多态性频率,计算其在胃癌患者中的分布。分别在共显性、显性、隐性模型下基因型与疾病进展的关系采用非条件Logistic回归分析,并计算OR值及其95%CI。采用Kaplan-Meier法绘制生存曲线,经Log Rank检验。结果82例患者中57例(69.5%)为男性,25例(30.5%)为女性,较为符合胃癌发病率男性多于女性的特征。患者中位年龄60.5岁。病理分化为低分化患者有54例(65.9%),中-高分化患者有28例(34.1%)。可确定T分期患者79例,其中T1-2患者6例(8%),T3-4患者73例(92%)。经Logistic回归分析,KDR基因的RS7692791位点的CT基因型为化疗不敏感的危险因素,携带CT基因型的患者化疗不敏感的风险较携带TT基因型患者高(OR=3.798,95%CI=1.061-13.587,P=0.040),显性模型下(TT/CT+CC),基因型和化疗敏感性存在关联(OR=3.491,95%CI=1.013-12.029,P=0.048),野生型患者对化疗较敏感。其余各位点基因多态性与化疗敏感性无关联(P0.05)。生存分析显示,KDR基因的RS2305948位点的显性模型中(CC/CT+TT),野生纯合CC基因型的PFS较长,为5个月,而突变型CT+TT基因型的PFS为2.5个月,差异有统计学意义(x2=4.268,P=0.039),NRP-1基因的RS2273466位点的隐性模型中(AA+GA/GG),突变纯合型GG的PFS较短,仅为1.5个月,而AA+GA的PFS为4.5个月,差异有统计学意义(x2=5.643,P=0.018)。各位点与OS均无关联。结论1.KDR基因的RS7692791位点的CT基因型为化疗不敏感的危险因素,显性模型下野生CC基因型一线化疗疗效较突变型CT+TT好,提示此位点可能与化疗敏感性相关。2.KDR基因的RS2305948位点的野生型拥有较长的PFS,提示其多态性可能影响晚期胃癌患者的PFS。3.NRP-1基因的RS2273466位点的突变纯合子基因型的PFS较短,提示其多态性与晚期胃癌患者的PFS可能有密切关系。
[Abstract]:Background and objective: gastric cancer is the most common malignant tumor of digestive tract, the highest incidence and mortality rate of second.NRP-1 of malignant tumor in our country is an important type transmembrane protein involved in tumor occurrence, development, it is mainly through 3 ways to participate in the regulation of tumor biological activity: VEGF-VEGFR2 pathway, PDGF-PDGFR pathway, NRP-1-ABL pathway is found. Its biological effects include, promote tumor development, promote tumor angiogenesis and promote tumor invasion and migration, involved in the regulation of tumor to chemotherapy drugs sensitivity. Single nucleotide polymorphism is the third generation of genetic markers, the differences between the different alleles of the same only a few nucleotide sites or only small insertion, deletion, can directly affect the protein expression and function, its genetic stability, wide distribution, frequency statistical analysis, easy, suitable The advantages of large-scale screening. The present study showed that individual differences in gastric cancer, genetic factors play a great role. But the current SNP study associated with gastric cancer is still mainly concentrated in the aspects of disease susceptibility, sensitivity in chemotherapy of advanced gastric cancer is still a lack of relevant research. This study is based in advanced gastric cancer at present, combined with the latest techniques, analysis of the relationship between SNP and the treatment of advanced gastric cancer NRP-1 gene pathway and part in from the DNA level, hoping to provide possible markers for predicting chemotherapy sensitivity, in order to achieve individualized treatment. Chemotherapy in patients with advanced gastric cancer materials and methods from January 2010 to May 2016 in the Second Affiliated Hospital of Dalian Medical University, a total of 82 cases, remove the pathological paraffin specimens, using QIAamp DNA FFPE Tissue Kit DNA. Extraction Kit Select label SNP site of the target gene in NCBI 1000 genome projects SNP public database, according to the location and literature were screened by the method of SNaPshot sequencing, gene polymorphisms were detected. According to the clinical information of clinical data of patients were collected, and through clinical follow-up and telephone follow-up to further improve the relevant information. The curative effect of chemotherapy in patients with evaluation of the use of RECIST standard. According to the different groups of patients with clinical data, analysis of the polymorphism frequency of each site using SPSS 22 statistical software to calculate the distribution of patients with gastric cancer. In CO dominant, dominant, relationship between genotype and disease progress under the recessive model using non conditional Logistic regression analysis, and to calculate the value of OR and 95%CI. using Kaplan-Meier method to draw survival curves by Log Rank test. Results in 82 cases, 57 cases (69.5%) were male, 25 cases ( 30.5%) for women, more in line with the characteristics of gastric cancer incidence was higher in males than in females. The median age was 60.5 years. The pathological differentiation is poorly differentiated in 54 patients (65.9%), middle high differentiation in 28 patients (34.1%). Determine the T staging of patients with 79 cases, including 6 cases of T1-2 patients (8%), 73 cases of T3-4 patients (92%). Logistic regression analysis showed that the CT genotype of RS7692791 KDR gene was not sensitive to chemotherapy risk factors, the risk is not sensitive to chemotherapy in patients with CT genotype than in TT genotype patients (OR=3.798,95%CI=1.061-13.587, P=0.040), under the dominant model (TT/CT+CC), association genotype and sensitivity to chemotherapy (OR=3.491,95%CI=1.013-12.029, P=0.048), wild type patients are sensitive to chemotherapy. No correlation between other every gene polymorphisms and sensitivity to chemotherapy (P0.05). Survival analysis showed that the dominant model of RS2305948 sites of KDR gene (CC/CT+TT) in the wild. Born in homozygous CC genotype PFS is longer, for 5 months, but the mutant CT+TT genotype PFS was 2.5 months, the difference was statistically significant (x2=4.268, P=0.039), hidden RS2273466 model in the NRP-1 gene (AA+GA/GG), homozygous mutation of GG PFS is short, only 1.5 month, AA+GA and PFS for 4.5 months, the difference was statistically significant (x2=5.643, P=0.018). You and OS had no correlation. The CT genotype of 1.KDR gene locus RS7692791 conclusion the danger is not sensitive to chemotherapy, the dominant model under the effect of the wild-type CC genotype is the first-line chemotherapy of mutant CT+TT. Wild type RS2305948 sites suggest that this locus may be associated with chemotherapy sensitivity of.2.KDR gene with longer PFS, suggesting that the polymorphism may affect RS2273466 locus of PFS.3.NRP-1 gene in patients with advanced gastric cancer mutation in the homozygous genotype PFS is short, presenting its polymorphism with advanced gastric PFS in cancer patients may have a close relationship.

【学位授予单位】：大连医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.2

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