食管鳞状细胞癌TP53突变研究

发布时间：2018-05-11 03:43

  本文选题：食管鳞癌 + TP53　； 参考：《郑州大学》2017年硕士论文

【摘要】：研究背景食管癌是常见的消化道恶性肿瘤之一。在我国,食管癌的主要组织学类型是鳞状细胞癌,主要发生在食管的中段。我国每年新发食管癌27.7万人,位居恶性肿瘤新发病例数第6位,因食管癌死亡人数为20.6万,位居恶性肿瘤相关性死亡第4位。TP53基因分为野生型和突变型,野生型TP53基因为抑癌基因,其编码的p53蛋白可通过细胞周期阻滞、促进DNA损伤修复及诱导凋亡的方式抑制恶性肿瘤的发生。TP53基因发生突变后,由于空间构象改变影响到转录活化功能及p53蛋白的磷酸化过程,不仅失去了野生型p53抑制肿瘤增殖的作用,而且突变本身又使该基因具备癌基因功能。研究表明超过50%的恶性肿瘤中存在TP53突变。目的旨在探讨TP53在食管鳞癌患者中的突变频率及突变位点,以及TP53突变与年龄、性别、临床分期、淋巴结转移、分化程度、吸烟和饮酒之间的关系,为后续针对食管癌TP53突变的靶向治疗提供理论依据。方法收集2014年10月~2015年6月就诊于郑州大学第一附属医院行手术治疗的食管鳞癌患者术后标本共118例,每例患者取肿瘤组织大小约0.5cm,依次进行编号标记。提取组织标本的DNA,PCR扩增第5-8外显子,使用sanger测序技术,检测食管鳞癌组织中TP53突变频率及突变位点,并分析TP53突变与年龄、性别、临床分期、淋巴结转移、分化程度、吸烟和饮酒之间的关系。结果共检测118例食管鳞癌标本,其中TP53基因至少有1个外显子突变的有55例,总突变率为46.6%(55/118)。TP53基因有2个外显子突变的有4例,突变率为3.4%(4/118)。118例食管鳞癌标本共计有59个突变位点,其中,有38个位点发生错义突变,占总突变的64.4%(38/59);14个位点发生移码突变,占总突变的23.7%(14/59);7个位点发生无义突变,占总突变的11.9%(7/59)。最常见的突变为碱基C→T的转换,占总突变的22.0%(13/59)。第5号外显子的突变频率最高,为35.6%(21/59),第6、7、8号外显子位点发生突变频率分别为23.7%(14/59)、22.0%(13/59)和15.3%(9/59)。使用卡方检验分析得出食管鳞癌TP53突变与性别、年龄、临床分期、分化程度、淋巴结转移、居住地及食管癌家族史无相关性。使用比值比(Odd Ratios,ORs)计算得出重度吸烟/重度饮酒的食管鳞癌患者发生TP53突变的风险明显高于不吸烟/不饮酒患者。结论(1)食管鳞癌患者TP53基因发生至少1个外显子突变的概率为46.6,发生2个外显子突变的概率为3.4%;(2)食管鳞癌患者TP53突变与临床病理特征无相关性,而与重度吸烟/重度饮酒相关
[Abstract]:Background esophageal carcinoma is one of the most common malignant tumors of digestive tract. Squamous cell carcinoma (SCC) is the main histological type of esophageal carcinoma in China, which mainly occurs in the middle part of esophagus. There are 277000 new cases of esophageal cancer in China every year, which ranks sixth in the number of new cases of malignant tumors, 206000 deaths due to esophageal cancer, and the fourth highest number of deaths associated with malignant tumors. TP53 gene is classified into wild type and mutant type. The wild-type TP53 gene is a tumor suppressor gene, which encodes p53 protein through cell cycle arrest, promotes the repair of DNA damage and induces apoptosis, inhibits the mutation of .TP53 gene in malignant tumor. Because the spatial conformation change affects the transcriptional activation function and the phosphorylation process of p53 protein, it not only loses the function of wild-type p53 inhibiting tumor proliferation, but also makes the gene have the function of oncogene itself. Studies have shown that more than 50% of malignant tumors have TP53 mutations. Objective to investigate the mutation frequency and mutation site of TP53 in patients with esophageal squamous cell carcinoma, and the relationship between TP53 mutation and age, sex, clinical stage, lymph node metastasis, differentiation, smoking and alcohol consumption. To provide a theoretical basis for the subsequent targeted therapy of TP53 mutation in esophageal carcinoma. Methods 118 postoperative specimens of esophageal squamous cell carcinoma were collected from October 2014 to June 2015 in the first affiliated Hospital of Zhengzhou University. The tumor tissue size of each patient was about 0.5 cm. Exon 5-8 was amplified from tissue samples by DNA-polymerase chain reaction. TP53 mutation frequency and mutation site in esophageal squamous cell carcinoma tissues were detected by sanger sequencing, and TP53 mutation and age, sex, clinical stage, lymph node metastasis and differentiation were analyzed. The relationship between smoking and drinking. Results A total of 118 esophageal squamous cell carcinoma samples were detected, 55 of which had at least one exon mutation in TP53 gene, 4 had mutation rate of 2 exons in 46.6%(55/118).TP53 gene, and 59 mutation sites were found in 3. 4% / 118 esophageal squamous cell carcinoma samples. Among them, 38 loci have missense mutations, accounting for 64.44% of the total mutations, 14 loci have frameshift mutations, accounting for 23.714 / 59% of the total mutations, and 7 loci have nonsense mutations, accounting for 11.9B / 59% of the total mutations. The most common mutation was the conversion of base C T, which accounted for 22.0% of the total mutation and accounted for 13 / 59% of the total mutation. The mutation frequency of exon 5 was the highest at 35.6U / 21 / 59, and the mutation frequency at exon 6 / 7 and exon 8 was 23.714 / 59 / 22.0 and 15.3 / 59, respectively. The results of chi-square test showed that there was no correlation between TP53 mutation and sex, age, clinical stage, differentiation, lymph node metastasis, residence and family history of esophageal carcinoma. The risk of TP53 mutation in heavy smoking / heavy drinking esophageal squamous cell carcinoma patients was significantly higher than that in non-smoking / non-drinking patients. Conclusion the probability of at least one exon mutation of TP53 gene in esophageal squamous cell carcinoma patients is 46.6, and the probability of two exon mutations is 3.4x2) there is no correlation between TP53 mutation and clinicopathological characteristics in esophageal squamous cell carcinoma patients, but it is related to heavy smoking and heavy drinking.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.1
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本文编号：1872287