三羧酸循环通路关键基因单核苷酸多态性与大肠癌预后的相关性研究

发布时间：2018-07-07 14:02

本文选题：大肠癌(CRC) + 三羧酸循环基因　；参考：《第四军医大学》2015年硕士论文

【摘要】：研究背景大肠癌(colorectal cancer,CRC)是第三大恶性肿瘤,是全球癌症发病率和死亡率的主要原因,最近,在原来一些发病率相对较低的地方发现大肠癌的发病率有上升趋势,尤其是中国。近年来,遗传因素在大肠癌发生及进展中的作用越来越多地为人们所关注,其中单核苷酸多态性(Single nucleotide polymorphism,SNP)是反应人类遗传背景最常见的变异形式。但到目前为止,与大肠癌预后显著相关的SNP位点少见报道,同时,由于SNP在人群、种属之间的遗传差异,国外研究的显著性SNP位点在我国汉族人群中未必能够得到验证。所以,寻找能够评估我国汉族人群大肠癌预后更加特异、敏感的SNP位点成为亟待解决的问题。代谢改变是肿瘤的十大特征之一并显著影响肿瘤的发生及进展。三羧酸循环(Tricarboxylic acid,TCA)是线粒体内三大营养物质(糖类、脂类、氨基酸)的共同代谢通路。琥珀酸脱氢酶(Succinate dehydrogenase,SDH)、异柠檬酸脱氢酶(Isocitrate dehydrogenase,IDH)和延胡索酸水合酶(Fumarate hydratase,FH)是羧酸循环通路内的三个关键限速酶,随着人们对肿瘤相关分子机制认识的不断深入,越来越多的证据表明三羧酸循环通路分子SDH、IDH、FH在多种肿瘤的发生及进展中发挥着重要作用。多项研究证实用Si-RNA抑制IDH2表达可以抑制大肠癌细胞生长,而过表达该基因明显促进细胞增殖。细胞和动物实验均发现了SDHB表达下调与大肠癌组织分化相关且上调SDHB可以抑制大肠癌细胞生长与增殖。人群研究中也陆续报道了SDH、IDH、FH基因突变且直接或间接证据表明上述突变与大肠癌发生及进展相关,但目前国内外尚未开展上述基因SNP位点与大肠癌预后方面的研究。研究目的探讨三羧酸循环通路中SDH、IDH和FH基因的功能性SNPs位点与大肠癌预后的相关性,为大肠癌预后评估提供潜在的分子标志物。研究方法我们以在第四军医大学唐都医院及西京医院接受大肠癌根治手术且未接受术前治疗的患者为研究对象,采用前瞻性队列研究方法,自2006年5月开始采集血液样本,同时系统收集临床信息并进行规范化随访,截止2012年6月累计收集具有齐全临床信息的大肠癌血液样本697例。然后选取SDH、IDH和FH中的16个功能性SNPs位点,利用飞行时间质谱生物芯片系统(Mass ARRAY?)进行SNP分型检测,结合临床信息及随访资料,对SNP位点与CRC预后关系进行统计学分析。研究结果1、我们在2个基因上发现了4个SNP位点(SDHC rs12064957、SDHC rs4131826、SDHD rs544184、SDHD rs7121782)与大肠癌(CRC)生存生存风险显著相关;在3个基因上发现了5个SNP位点(SDHC rs4131826,SDHD rs10789859、rs544184、rs7121782,FH rs12071124)与大肠癌(CRC)复发风险显著相关;2、在进一步的累积效应分析中我们发现,危险基因型数在大肠癌(CRC)的死亡和复发风险分析中呈现明显的数量累积效应,(P均小于0.001);3、STREE软件对各显著SNPs位点进行生存树分析显示:SDHC基因中rs4131826位点是影响大肠癌(CRC)的死亡风险最重要的位点,FH基因rs12071124位点是影响复发风险最重要的位点。研究结论我们的研究提示:三羧酸循环通路代谢酶基因功能性SNPs可能与大肠癌患者预后明显相关,该结论仍需进一步的功能学验证以提高临床应用价值。
[Abstract]:Background colorectal cancer (CRC) is the third major malignant tumor, which is the main cause of global cancer incidence and mortality. Recently, the incidence of colorectal cancer is rising in some places with relatively low incidence, especially in China. In recent years, the role of genetic factors in the occurrence and progress of colorectal cancer is increasing. The more people are concerned, the Single nucleotide polymorphism (SNP) is the most common variant of the human genetic background. But so far, the SNP site, which is significantly related to the prognosis of colorectal cancer, is rarely reported. At the same time, because of the genetic differences between SNP in the human group and among the species, the significant SNP in the study abroad. The loci may not be verified in the Han population of our country. So it is an urgent problem to find a more specific and sensitive SNP locus to evaluate the prognosis of colorectal cancer in the Han population. Metabolic changes are the ten major features of the tumor and significantly affect the occurrence and development of the tumor. The three carboxylic acid cycle (Tricarboxylic acid, TCA) is a line. The three major nutrients (carbohydrates, lipids, amino acids) in the body are common metabolic pathways. Succinic dehydrogenase (Succinate dehydrogenase, SDH), ISO citrate dehydrogenase (Isocitrate dehydrogenase, IDH) and fumaric acid hydrate enzyme (Fumarate hydratase, FH) are the three key speed limiting enzymes in the carboxic acid cycle pathway. More and more evidence shows that the three carboxylic acid cycle pathway molecules SDH, IDH, and FH play an important role in the development and progression of various tumors. Many studies have shown that Si-RNA inhibition of IDH2 expression can inhibit the growth of colorectal cancer cells, and the overexpression of this gene can significantly promote cell proliferation. Cell and animal experiments It was found that the down regulation of SDHB expression was associated with the differentiation of colorectal carcinoma tissue and the up regulation of SDHB could inhibit the growth and proliferation of colorectal cancer cells. In the population study, the mutations of SDH, IDH, FH gene were also reported, and the direct or indirect evidence showed that the above mutation was related to the occurrence and progression of colorectal cancer. However, the SNP locus of the above gene has not been carried out at home and abroad. Study on the prognosis of colorectal cancer. Objective to explore the correlation between the functional SNPs loci of SDH, IDH and FH genes in the three carboxylic acid circulation pathway and the prognosis of colorectal cancer, and provide a potential molecular marker for the prognosis evaluation of colorectal cancer. A prospective cohort study was used to collect blood samples from May 2006, and a systematic collection of clinical information and standardized follow-up was conducted in May 2006. 697 cases of large intestine cancer with complete clinical information were collected in June 2012 and 16 functions in SDH, IDH and FH were selected. The sex SNPs site, using the time of flight mass spectrometry biochip system (Mass ARRAY?) for SNP typing, combined with clinical information and follow-up data, analyzed the relationship between the SNP site and the CRC prognosis. 1, we found 4 SNP loci on the 2 genes (SDHC rs12064957, SDHC rs4131826, SDHD) and The survival and survival risk of colorectal cancer (CRC) was significantly correlated; 5 SNP loci (SDHC rs4131826, SDHD rs10789859, rs544184, rs7121782, FH rs12071124) were found to be significantly associated with the recurrence risk of colorectal cancer (CRC) on 3 genes; and 2, in further analysis of cumulative effects, we found that the number of dangerous genotypes in colorectal cancer (CRC) death and recurrent winds A significant cumulative effect was presented in the risk analysis, (P was less than 0.001). 3, STREE software showed that the rs4131826 site in the SDHC gene was the most important site for the death risk of colorectal cancer (CRC), and the FH gene rs12071124 site was the most important site affecting the risk of recurrence. The conclusion of the study is that we have found that the FH gene is the most important site affecting the risk of recurrence. It is suggested that the functional SNPs of the metabolic enzyme gene of the three carboxylic acid cycle pathway may be significantly associated with the prognosis of patients with colorectal cancer. This conclusion still needs further functional validation to improve the clinical value.
【学位授予单位】：第四军医大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R735.34

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