PTPN11基因多态性与胃癌患者预后的研究

发布时间：2018-05-27 23:34

本文选题：胃癌 + 单核苷酸多态性　；参考：《吉林大学》2017年硕士论文

【摘要】：胃癌是人类常见的恶性肿瘤,2012年全球约有95.2万新发胃癌病例,72.3万胃癌死亡病例,分别占恶性肿瘤发病率的第五位和死因第三位。尽管在发达国家的胃癌发病率和死亡率均呈现下降趋势,但在我国仍然居高不下。2012年我国胃癌新发病例数为42.4万,死亡病例数为29.8万,均占全球的40%以上。目前随着胃癌诊断技术的提高和术后放化疗方案的进展,胃癌患者术后生存率有所提高,但术后5年生存率仅为27.4%。研究发现即使处于相同的病理分期并接受相同的手术及术后治疗的胃癌患者,其术后生存时间也存在差异,提示胃癌患者的预后可能与个体的遗传背景有关。原癌基因蛋白酪氨酸磷酸酶非受体型11(PTPN11)编码蛋白酪氨酸磷酸酶2(SHP2),在多种肿瘤组织中高表达,与多种肿瘤的发生、发展和预后密切相关。目前已有研究表明PTPN11基因多态性(SNPs)与多种肿瘤的发生有关,对于肿瘤预后的评估关注较少。本研究在中国胃癌高发地区的东北地区开展PTPN11基因变异与胃癌预后的研究,揭示PTPN11基因多态性作为肿瘤标志物用于评估胃癌患者术后长期生存的可能性。目的:本研究选择中国东北地区接受胃癌切除术的患者作为研究对象,探讨中国北方汉族人群PTPN11基因单核苷酸多态性与胃癌患者术后长期生存的关系,以及PTPN11基因多态性对SHP2蛋白表达的影响,为胃癌患者实施个性化精准化治疗提科学的理论依据。方法:本研究选取2008年6月至2010年11月就诊于吉林大学第一医院,接受胃肿瘤切除术并经病理学确诊为胃癌的388例患者为研究对象。应用Taq Man基因分型技术检测PTPN11上5个SNPs位点(rs2301756、rs12423190、rs12229892、rs4767860和rs7958372)的基因型分布,应用免疫组织化学技术检测93例胃癌组织中的SHP2蛋白表达水平。Kaplan-Meier法绘制生存曲线,log-rank检验比较不同基因型患者间术后生存时间的差异,应用单因素和多因素Cox回归模型计算风险比(HR)及95%可信区间(95%CI)。结果:(1)本研究最终纳入363例胃癌患者进行生存分析,中位随访时间为60.7个月;单因素Cox回归分析结果显示,与PTPN11基因rs2301756 CC基因型比较,携带CT基因型的胃癌患者术后生存时间更短,死亡风险更高(HR=1.78,95%CI:1.26-2.52,P=0.001),尚未发现其余4个位点的基因多态性与胃癌患者预后存在关联。肿瘤直径≥5cm(P0.001)、T3/T4、N2/N3、TNM分期为II/III期(P0.05),存在脉管浸润或神经浸润(P0.001)的胃癌患者预后较差。(2)多因素Cox回归分析调整混杂因素结果提示,虽然携带rs2301756位点CT基因型的胃癌患者比携带CC基因型胃癌患者术后死亡风险者增加了40%(HR=1.40,95%CI:0.98-2.00),显示了增加的趋势,但尚未达到具有统计学意义的关系(P=0.064)。肿瘤TNM高分期(II/III)是影响胃癌患者预后的独立危险因素。(3)免疫组织化学结果显示,胃癌组织中5个SNPs的不同基因型间的SHP2蛋白表达的水平均无统计学差异(P0.05)。结论:PTPN11 rs2301756基因多态性可能作为胃癌患者术后长期生存预测的生物标记物,但仍需在大样本人群中进行长期随访来验证。
[Abstract]:Gastric cancer is a common human malignant tumor. In 2012, there were about 95.2 million new cases of gastric cancer and 723 thousand cases of cancer death, which accounted for fifth of the incidence of malignant tumors and third of the causes of death, respectively. Although the incidence and mortality of gastric cancer in developed countries were declining, the new incidence of gastric cancer in China was still high in China for.2012 years. The number of cases was 424 thousand and the number of deaths was 298 thousand, accounting for more than 40% of the world. With the improvement of the diagnosis of gastric cancer and the progress of postoperative radiotherapy and chemotherapy, the survival rate of patients with gastric cancer was improved, but the survival rate of 5 years after the operation was only 27.4%. study found that the same pathological staging and the same operation and postoperative treatment were found. The survival time of the patients with gastric cancer is also different, suggesting that the prognosis of the patients with gastric cancer may be related to the genetic background of the individual. The proto oncogene protein tyrosine phosphatase 11 (PTPN11) encoded protein tyrosine phosphatase 2 (SHP2) is highly expressed in a variety of tumor tissues, closely related to the occurrence, development and prognosis of a variety of tumors. Research has shown that PTPN11 gene polymorphism (SNPs) is related to the occurrence of a variety of tumors and is less concerned about the prognosis of cancer. This study carried out the study of PTPN11 gene variation and prognosis of gastric cancer in the northeast region of the high incidence area of China's gastric cancer, and revealed that the polymorphism of PTPN11 gene was used as a tumor marker to evaluate the patients with gastric cancer. Objective: To investigate the possibility of long-term survival. Objective: To investigate the relationship between the single nucleotide polymorphism of PTPN11 gene and the long-term survival of the patients with gastric cancer, and the effect of the PTPN11 gene polymorphisms on the expression of SHP2 protein in the northeastern Chinese Han population, and the effect of the polymorphisms of the gene on the expression of SHP2 protein in the Chinese northeastern Han population. In this study, 388 Cases of gastric cancer were diagnosed as gastric cancer from June 2008 to November 2010, and 5 SNPs loci on PTPN11 (rs2301756, rs1242) were detected by Taq Man genotyping technique. The genotypic distribution of 3190, rs12229892, rs4767860 and rs7958372) was used to detect the survival curve of the SHP2 protein expression level in 93 cases of gastric cancer by immunohistochemistry. The difference of postoperative survival time between patients with different genotypes was compared by log-rank test, and the risk of single factor and multiple factor Cox regression model was used to calculate the risk. Results: (HR) and 95% confidence interval (95%CI). Results: (1) the survival analysis of 363 cases of gastric cancer was finally included in this study. The median follow-up time was 60.7 months. The results of single factor Cox regression analysis showed that compared with the PTPN11 gene rs2301756 CC genotype, the survival time of the patients carrying the CT genotype was shorter and the death risk was higher (HR=1.78,95). %CI:1.26-2.52, P=0.001), the gene polymorphism of the remaining 4 loci was not found to be associated with the prognosis of gastric cancer patients. The tumor diameter was more than 5cm (P0.001), T3/T4, N2/N3, TNM stage was II/III phase (P0.05), and the prognosis of gastric cancer patients with vascular infiltration or nerve infiltration (P0.001) was poor. (2) multifactor Cox regression analysis adjusted the results of confounding factors, Although the cancer patients carrying the rs2301756 locus CT genotype increased by 40% (HR=1.40,95%CI:0.98-2.00) than those with the risk of postoperative death in the patients with CC genotypic gastric cancer, the increased trend was shown, but there was no statistically significant relationship (P=0.064). The tumor TNM high stage (II/III) was an independent risk factor for the prognosis of gastric cancer patients. (3) the immunohistochemical results showed that there was no significant difference in the level of SHP2 protein expression between different genotypes of SNPs in gastric carcinoma (P0.05). Conclusion: the PTPN11 rs2301756 gene polymorphism may be used as a biomarker for long-term survival prediction of gastric cancer patients, but it still needs long-term follow-up in large sample population to verify.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.2

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