线粒体DNA拷贝数与头颈部肿瘤发病风险的病例—对照研究

发布时间：2018-01-02 01:24

本文关键词：线粒体DNA拷贝数与头颈部肿瘤发病风险的病例—对照研究　出处：《南京医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：头颈部肿瘤(Head and neck carcinoma,HNC)为全球范围内第六大常见肿瘤类型,约占全部恶性肿瘤的6%。每年新发病例超过60万,其中2/3在发展中国家。头颈部肿瘤主要起源于上呼吸道、上消化道黏膜,包括口腔、咽(鼻咽、口咽、喉咽)及喉部,其中约90%的病理类型是鳞状细胞癌(Head and neck squamous cell carcinoma,HNSCC)。除鼻咽癌(与EB病毒感染有关)以外,吸烟、饮酒以及HPV感染等通常被认为是头颈部鳞癌的重要危险因素。线粒体中进行的有氧呼吸和氧化磷酸化过程是真核细胞的主要能量来源。通过参与能量和物质代谢等过程,线粒体影响着真核细胞和生物的生长、发育以及功能实现等众多方面。影响线粒体的遗传物质统称为线粒体基因组,包括部分核DNA和线粒体DNA,二者的共同作用才能确保线粒体发挥正常的功能。相对于核DNA,线粒体DNA由于其特殊的结构和高浓度活性氧外环境,更容易发生突变,突变率高出10-200倍。线粒体DNA中的点突变以及拷贝数变异都可能导致线粒体的功能异常。线粒体功能异常会抑制细胞的氧化磷酸化过程,导致机体内ROS大量产生和富集,从而引起机体氧化应激反应和核DNA与线粒体DNA突变与损伤,最终引起和促进肿瘤的发生。正常组织中会因为能量需求的不同,导致组织间线粒体DNA拷贝数的差异,但是同一种组织中拷贝数会相对保持稳定,以维持正常的生理功能。线粒体DNA拷贝数可以受到遗传因素和环境因素两方面共同调控,其变化一定程度上反映了年龄、吸烟、氧化损伤反应等多种影响肿瘤发生发展的因素对细胞、组织以及机体的作用情况。因此线粒体DNA拷贝数有可能成为一种预测肿瘤发生风险的生物标志物。目前,多篇流行病学研究已经对外周血中线粒体DNA拷贝数与不同肿瘤发病风险的关系进行了探讨,但这些研究结论相互之间并不一致。6篇报道线粒体DNA拷贝数与头颈部鳞癌以及癌前病变发病风险关联的研究相互之间的结果也不一致。因此,还需要进一步开展大样本研究明确线粒体DNA拷贝数与头颈部鳞癌发病风险之间的关系。本研究采用病例对照设计研究外周血线粒体DNA拷贝数与头颈部鳞癌发病风险的关系。病例为江苏地区医院来源的570例新发头颈部鳞癌病例,对照样本为来源于江苏地区社区慢病筛查人群的597例健康个体。采用定量PCR方法检测线粒体DNA拷贝数,利用特异性引物分别扩增同一个体外周血线粒体DNA中ND1序列的拷贝数和核基因HGB序列拷贝数,通过ND1序列和HGB序列拷贝数的比值相对定量线粒体DNA拷贝数。采用盲法、复孔平行设置和重复检测等质量控制措施以保证线粒体DNA拷贝数检测的准确性。采用Logistic回归模型以及限制性立方样条函数分析线粒体DNA拷贝数与头颈部鳞癌发病风险的关联,计算比值比(OR)和95%可信区间(95%CI)。研究结果显示,病例组线粒体DNA拷贝数的中位值为4.33(1.38-29.85),对照组的中位值为3.50(1.93-11.19),前者高于后者,差异有统计学意义(P=0.016)。按照对照组线粒体DNA拷贝数值将研究对象四等分为四组,关联分析结果显示,头颈部鳞癌发病风险与线粒体DNA拷贝数之间呈U型相关。以线粒体DNA拷贝数第二等分位点线粒体DNA拷贝数个体作为对照组,第一等分位点和第四等分位点的个体其头颈部鳞癌发病风险显著增加,OR(95%CI)值分别为1.95(1.37-2.76)和2.16(1.53-3.04)。此外,限制性立方样图的结果发现二者关联成U型相关。本研究在中国汉族人群中探讨了线粒体DNA拷贝数变化与头颈部鳞癌发病风险之间的关联,发现线粒体DNA拷贝数过高或者过低都有可能与头颈部鳞癌发病风险升高有关。本次研究的结论为指导头颈部鳞癌高危人群的筛查和早期诊断提供了理论和技术支持,也为进一步研究头颈部鳞癌发病机制提供了一定线索。
[Abstract]:Head and neck neoplasms (Head and neck carcinoma, HNC) is the sixth most common cancer worldwide, accounting for all malignant tumor 6%. more than 600 thousand new cases each year, of which 2/3 in the developing world. Head and neck cancer mainly originated from the upper respiratory tract, gastrointestinal tract, including the mouth, pharynx (nasopharynx, oropharynx, hypopharynx) and the throat, which is about 90% of the pathological types of squamous cell carcinoma (Head and neck squamous cell carcinoma, HNSCC). In addition to nasopharyngeal carcinoma (with EB infection), smoking, drinking and HPV infection is usually considered as an important risk factor of head and neck squamous cell carcinoma. The mitochondria of aerobic respiration and oxidative phosphorylation the acidification process is the main energy source in eukaryotic cells. Through participation in energy and material metabolism, mitochondrial affects eukaryotic cell and organism growth, development and function realization etc. the influence line of grain The genetic material called mitochondrial genome, including nuclear DNA and mitochondrial DNA, the two work together to ensure the proper functioning of mitochondria. The mitochondrial DNA relative to nuclear DNA, because of its special structure and high concentration of active oxygen and external environment, more prone to mutation, the mutation rate is 10-200 times higher. Mitochondrial DNA the point mutation and copy number variation may lead to mitochondrial dysfunction. Mitochondria oxidative phosphorylation dysfunction can inhibit cell, cause the body to produce a large number of ROS and concentration, causing oxidative stress response and nuclear DNA and mitochondrial DNA mutations and ultimately cause injury, and promote tumorigenesis. In normal tissue because the energy demand is different, resulting in differences in the copy number of mitochondrial DNA among organizations, but the same kind of organization in copy number will be relatively stable, in order to maintain the normal physiological The function of mitochondrial DNA copy number. Can control two aspects by genetic and environmental factors, the change reflects the age, smoking, oxidative damage reaction such as influence factors on the occurrence and development of tumor cells, tissue and body. Therefore the role of mitochondrial DNA copy number may be a biomarker to predict the risk for cancer. At present, the relationship between mitochondrial DNA copy number and different tumor risk many epidemiological studies have in peripheral blood are discussed, but these research conclusions are not consistent between the.6 report of mitochondrial DNA copy number and the results of head and neck squamous cell carcinoma and precancerous lesions of the risk correlation between them is inconsistent. Therefore, still need further large sample study of mitochondrial DNA copy number and the relationship between squamous cell carcinoma of head and neck cancer risk. This study used a case-control design study of peripheral blood mitochondrial DNA copy number and HNSCC risk. Patients in hospitals of Jiangsu area from 570 new cases of head and neck squamous cell carcinoma cases, the control samples from the Jiangsu area community chronic disease. Among 597 cases of healthy individuals. By quantitative PCR method of mitochondrial DNA detection of copy number, the same sequence of ND1 were amplified in peripheral blood mitochondrial DNA using specific primers and copies of nuclear gene HGB sequence copy number by ND1 sequence and HGB sequence copy number ratio of the relative quantification of mitochondrial DNA copy number. Using blind method, the complex hole is arranged in parallel and repeated detection and quality control measures in order to ensure the accuracy of detection of mitochondrial DNA copy number. Analysis of mitochondrial DNA copy number and the risk of head and neck squamous cell carcinoma by Logistic regression model and restricted cubic spline function. Together, calculate the odds ratio (OR) and 95% confidence intervals (95%CI). The results showed that the cases of mitochondrial DNA copy number in a value of 4.33 (1.38-29.85), the control group for a median of 3.50 (1.93-11.19), the former is higher than the latter, the difference was statistically significant (P=0.016). According to the control group of mitochondria a copy of the DNA value will be four research objects are divided into four groups, correlation analysis showed that the risk of head and neck squamous cell carcinoma and mitochondrial DNA copy is U type. The number between mitochondrial DNA copy number second quantile of mitochondrial DNA copy number of individuals as the control group, significant increase in first and fourth quantile quantile of the head and neck the risk of squamous cell carcinoma, OR (95%CI) = 1.95 (1.37-2.76) and 2.16 (1.53-3.04). In addition, restricted cubic sample found two related to U. This study explores the China mitochondrial DNA in Han population Association between copy number variation and HNSCC risk, found that mitochondrial DNA copy number is too high or too low may be associated with increased risk of head and neck squamous cell carcinoma. The results of this research provide theoretical and technical support for the screening and early diagnosis of squamous cell carcinoma of head and neck guidance of high-risk groups, but also provides some clues for the study the pathogenesis of head and neck squamous cell carcinoma.

【学位授予单位】：南京医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R739.91

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