本文選題：食管鱗癌 + TP53��； 參考：《鄭州大學》2017年碩士論文

【摘要】：研究背景食管癌是常見的消化道惡性腫瘤之一。在我國,食管癌的主要組織學類型是鱗狀細胞癌,主要發(fā)生在食管的中段。我國每年新發(fā)食管癌27.7萬人,位居惡性腫瘤新發(fā)病例數第6位,因食管癌死亡人數為20.6萬,位居惡性腫瘤相關性死亡第4位。TP53基因分為野生型和突變型,野生型TP53基因為抑癌基因,其編碼的p53蛋白可通過細胞周期阻滯、促進DNA損傷修復及誘導凋亡的方式抑制惡性腫瘤的發(fā)生。TP53基因發(fā)生突變后,由于空間構象改變影響到轉錄活化功能及p53蛋白的磷酸化過程,不僅失去了野生型p53抑制腫瘤增殖的作用,而且突變本身又使該基因具備癌基因功能。研究表明超過50%的惡性腫瘤中存在TP53突變。目的旨在探討TP53在食管鱗癌患者中的突變頻率及突變位點,以及TP53突變與年齡、性別、臨床分期、淋巴結轉移、分化程度、吸煙和飲酒之間的關系,為后續(xù)針對食管癌TP53突變的靶向治療提供理論依據。方法收集2014年10月~2015年6月就診于鄭州大學第一附屬醫(yī)院行手術治療的食管鱗癌患者術后標本共118例,每例患者取腫瘤組織大小約0.5cm,依次進行編號標記。提取組織標本的DNA,PCR擴增第5-8外顯子,使用sanger測序技術,檢測食管鱗癌組織中TP53突變頻率及突變位點,并分析TP53突變與年齡、性別、臨床分期、淋巴結轉移、分化程度、吸煙和飲酒之間的關系。結果共檢測118例食管鱗癌標本,其中TP53基因至少有1個外顯子突變的有55例,總突變率為46.6%(55/118)。TP53基因有2個外顯子突變的有4例,突變率為3.4%(4/118)。118例食管鱗癌標本共計有59個突變位點,其中,有38個位點發(fā)生錯義突變,占總突變的64.4%(38/59);14個位點發(fā)生移碼突變,占總突變的23.7%(14/59);7個位點發(fā)生無義突變,占總突變的11.9%(7/59)。最常見的突變?yōu)閴A基C→T的轉換,占總突變的22.0%(13/59)。第5號外顯子的突變頻率最高,為35.6%(21/59),第6、7、8號外顯子位點發(fā)生突變頻率分別為23.7%(14/59)、22.0%(13/59)和15.3%(9/59)。使用卡方檢驗分析得出食管鱗癌TP53突變與性別、年齡、臨床分期、分化程度、淋巴結轉移、居住地及食管癌家族史無相關性。使用比值比(Odd Ratios,ORs)計算得出重度吸煙/重度飲酒的食管鱗癌患者發(fā)生TP53突變的風險明顯高于不吸煙/不飲酒患者。結論(1)食管鱗癌患者TP53基因發(fā)生至少1個外顯子突變的概率為46.6,發(fā)生2個外顯子突變的概率為3.4%;(2)食管鱗癌患者TP53突變與臨床病理特征無相關性,而與重度吸煙/重度飲酒相關
[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.
【學位授予單位】：鄭州大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R735.1
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本文編號：1872287