DNA甲基化生物标记物在恶性肿瘤中的转化应用

肿瘤的发生发展存在广泛的遗传变化和相关的基因功能及活动失调。其中表观遗传学中DNA甲基化是表征最好的表观遗传修饰之一,它影响基因表达和基因组稳定性,对肿瘤的发生发展具有重要影响。这些表观遗传变化大部分发生在肿瘤的早期,且在整个肿瘤类型中普遍存在,DNA甲基化标记物是肿瘤早期诊断、预后和治疗检测的重要方法。通过血液、粪便、尿液和其他生物样本中可以检测癌症相关的DNA甲基化变化,它是一种无创、快速和可重复的组织活检的替代方法。DNA 甲基化是可适用于人群筛查的简单、经济和高度特异性的癌症检测的重要手段,虽然面临许多挑战,但是 DNA甲基化生物标记物以独特的优势,具有临床转化应用的前景和价值。本文综述了DNA甲基化特征、作用机制,及在膀胱癌、乳腺癌、结直肠癌等肿瘤中的早期诊断、临床治疗效果及预后判定的最新研究进展,并讨论了临床转化存在的问题和展望。     

DNA甲基化与肿瘤

在肿瘤细胞中，ＤＮＡ甲基化状况的改变与基因的异常表达、基因突变、基因缺失重排和基因组印迹等遗传效应有关；这些遗传效应可能是癌基因激活和肿瘤抑制基因失活的诱因；因此，ＤＮＡ的异常甲基化可能与肿瘤的发生和发展都有关系。这为研究突变和癌变的分子机理提供了新思路。     

DNA甲基化与肿瘤

DNA甲基化参与基因的表达调控。 DNA甲基化异常与肿瘤等疾病有关 ,抑癌基因启动子区的异常甲基化和癌基因的去甲基化均影响肿瘤发生发展过程。肿瘤细胞的总体甲基化水平比正常细胞低 ,但是伴有某些Cp G岛甲基化程度增高     

DNA甲基化检测方法

DNA甲基化是真核细胞基因组重要修饰方式之一 ,参与基因的表达调控。目前 ,DNA甲基化检测的方法主要有 :酶切、限制性酶切 - PCR(restriction enzym e PCR)、甲基化特异性 PCR(methylation- specific PCR,MS PCR)、Southern印迹亚硫酸盐测序 (bisulfite DNA sequencing)、变性高效液相色谱 (denature high- perform ance liquid chrom atography,DHPL C)、甲基化敏感的单核苷酸引物延伸 (m ethylation- sensitive single nucleotide prim er extensio,MS- SNu PE)、PCR荧光变性曲线分析(PCR and fluorescence m elting curve analysis)、亚硫酸盐 PCR- SSCP(bisulfite- PCR- SSCP)、COBRA(combined bisulfite re-striction analysis)和 Methy L ight     

DNA甲基化修饰异常与肺癌

DNA甲基化是表观遗传学研究的重要内容之一,与多种肿瘤的发生、发展密切相关。近年研究发现,肺癌相关基因高甲基化及甲基化转移酶的表达异常与肺癌发生有重要关系。了解DNA甲基化修饰异常在肺癌发生机制中的作用,将有助于患者的早期预防、早期诊断和改善预后。     

DNA甲基化与细胞周期

细胞基因的遗传性及表遗传性变异所致细胞周期过程的改变是恶性肿瘤的重要发病机制。在诸多调控细胞周期的影响因素中,DNA甲基化造成的表观遗传改变逐渐引起了人们的重视。目前的研究发现,DNA甲基化与越来越多的细胞周期调控基因关系密切,但它们之间的确切作用机制仍不十分明确。本文就目前国内外关于DNA甲基化对细胞周期影响的研究进展作一综述。     

DNA甲基化与肿瘤

表观遗传指不涉及DNA序列改变的,可随细胞分裂而遗传的基因组修饰作用;DNA甲基化是其中研究最多的基因表达调节机制.异常DNA甲基化可致肿瘤发生,它亦是肿瘤基因诊断和治疗的靶点.文章介绍DNA甲基化基本概念、作用效果及其可能机制;并讨论异常DNA甲基化与肿瘤的关联,包括肿瘤中DNA异常甲基化原因、异常甲基化致瘤机制及基...     

精子DNA甲基化异常与男性不育

DNA甲基化/去甲基化是表观遗传学最重要的内容并可以控制基因的表达和印迹,越来越多的研究显示DNA甲基化异常与不育男性精子发生异常、特定肿瘤的发生、神经系统疾病、Rett综合征等有关.文章通过总结近来的相关研究资料来阐述精子发生过程中的DNA甲基化状态的改变,探讨精子DNA的甲基化异常与男性不育之间的联系,旨在为男性不...     

DNA甲基化作用与狼疮

ＤＮＡ甲基化作用与狼疮葛蒙梁，阎月（北京医院，北京１００００５）Ａｂｓｔｒａｃｔ：ＴｈｅｒｏｌｅｏｆｅｎｖｉｒｏｎｍｅｎｔａｌａｇｅｎｔｓｉｎｃａｕｓｉｎｇＤＮＡｍｅｔｈｙｌａｔｉｏｎａｂｎｏｒｍａｌｉｔｉｅｓａｎｄｔｈｅｅｆｆｅｃｔ：ｏｆＤＮＡｈｙ...     

DNA甲基化与肿瘤

DNA甲基化是真核细胞DNA正常的修饰方式,它由DNA甲基化酶催化发生.DNA甲基化后核苷酸顺序未变,而基因表达受影响,异常甲基化是肿瘤发生的重要原因.DNA甲基化作为表遗传[1](epigenetics)机制之一,在肿瘤发生发展机制的研究中越来越受到重视.     

DNA甲基化与组蛋白修饰在自身免疫性疾病中的研究进展

自身免疫性疾病(AID)是一类由异常免疫反应引起的对健康组织和细胞造成严重损害的慢性炎症性疾病.包括系统系红斑狼疮(SLE)、类风湿性关节炎(RA)、系统性硬化病(SSc)以及急性冠脉综合征(ACS)等.其发病机制尚未明确,近年来研究表明,表观遗传在AID的发病机制中起重要作用.因此,进一步了解DNA甲基化、组蛋白修饰与AID的关系,为AID的预防和治疗提供了新线索.     

Testosterone and coronary artery disease in men

Coronary artery disease (CAD) is the leading cardiovascular cause of death, and in men, endogenous testosterone concentrations are inversely related to the extent and severity of CAD. Testosterone is known to affect a number of risk factors for CAD and has effects on vascular tone, vasoreactivity and blood flow of blood vessels beyond the reproductive system, indicating that testosterone may be involved in the pathogenesis of CAD. In this review we will present and discuss the actions of endogenous testosterone and testosterone treatment on risk factors for CAD, on the blood vessel wall and blood flow, and on atheroma development and progression, and discuss the potential for testosterone use in men with CAD.     

Diabetes and chronic nitrate therapy as co-determinants of somatic DNA damage in patients with coronary artery disease

Somatic DNA damage has been linked to coronary artery disease (CAD). However, whether genetic instability is linked to CAD per se or to concomitant potentially genotoxic metabolic and pharmacological factors remains still unclear. The aim of this study was to evaluate the determinants of somatic DNA damage in a large population of patients undergoing coronary angiography. A total of 278 in-hospital patients (215 men, age 61.8±0.7 years) were studied by using micronucleus assay (MN) in human lymphocytes, which is one of the most commonly used biomarker for somatic DNA damage. Significant CAD (>50% diameter stenosis) was present in 210 patients (179 men, age 62.3±0.7 years). Normal coronary arteries were observed in 68 patients (35 men, age 60.2±1.7 years). There were no significant differences between patients with and without CAD, but patients with multivessel disease had the highest MN levels (P=0.01). MN frequency was also found significantly higher in presence of type 2 diabetes (P<0.0001), dyslipidemia (P=0.048) and nitrate therapy (P=0.0002). A significant additive effect was also observed between diabetes and nitrate therapy (P=0.02). On multivariate logistic regression analysis, diabetes [odds ratio =6.8 (95% confidence interval, 3.2–14.5), P<0.0001] and nitrate therapy [odds ratio =2.4 (95% confidence interval, 1.3–4.7), P=0.01] remained the only significant determinants for the 50th percentile of MN (>12). These results indicated that diabetes and, to a lesser extent, chronic nitrate therapy are major determinants of somatic DNA instability in patients with CAD. DNA damage might represent an additional pathogenetic dimension and a possible therapeutic target in the still challenging management of coronary artery disease concerning diabetics.     

DNA methylation in genes associated with the evolution of ageing and disease: A critical review

Ageing is characterised by a physical decline in biological functioning which results in a progressive risk of mortality with time. As a biological phenomenon, it is underpinned by the dysregulation of a myriad of complex processes. Recently, however, ever-increasing evidence has associated epigenetic mechanisms, such as DNA methylation (DNAm) with age-onset pathologies, including cancer, cardiovascular disease, and Alzheimer’s disease. These diseases compromise healthspan. Consequently, there is a medical imperative to understand the link between epigenetic ageing, and healthspan. Evolutionary theory provides a unique way to gain new insights into epigenetic ageing and health. This review will: (1) provide a brief overview of the main evolutionary theories of ageing; (2) discuss recent genetic evidence which has revealed alleles that have pleiotropic effects on fitness at different ages in humans; (3) consider the effects of DNAm on pleiotropic alleles, which are associated with age related disease; (4) discuss how age related DNAm changes resonate with the mutation accumulation, disposable soma and programmed theories of ageing; (5) discuss how DNAm changes associated with caloric restriction intersect with the evolution of ageing; and (6) conclude by discussing how evolutionary theory can be used to inform investigations which quantify age-related DNAm changes which are linked to age onset pathology.     

DNA methylation and autoimmune disease

DNA methylation plays an essential role in maintaining T-cell function. A growing body of literature indicates that failure to maintain DNA methylation levels and patterns in mature T cells can result in T-cell autoreactivity in vitro and autoimmunity in vivo. Defective maintenance of DNA methylation may be caused by drugs such as procainamide or hydralazine, or failure to activate the genes encoding maintenance DNA methyltransferases during mitosis, resulting in the development of a lupus-like disease or perhaps other autoimmune disorders. This paper reviews the evidence supporting a role for abnormal T-cell DNA methylation in causing autoimmunity in an animal model of drug-induced lupus, and discusses some of the mechanisms involved. T cells from patients with active lupus have evidence for most if not all of the same methylation abnormalities, suggesting that abnormal DNA methylation plays a role in idiopathic human lupus as well.     

Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients

Epigenetic dysregulation of gene expression is thought to be critically involved in the pathophysiology of Alzheimer's disease (AD). Recent studies indicate that DNA methylation and DNA hydroxymethylation are 2 important epigenetic mechanisms that regulate gene expression in the aging brain. However, very little is known about the levels of markers of DNA methylation and hydroxymethylation in the brains of patients with AD, the cell-type specificity of putative AD-related alterations in these markers, as well as the link between epigenetic alterations and the gross pathology of AD. The present quantitative immunohistochemical study investigated the levels of the 2 most important markers of DNA methylation and hydroxymethylation, that is, 5-methylcytidine (5-mC) and 5-hydroxymethylcytidine (5-hmC), in the hippocampus of AD patients (n = 10) and compared these to non-demented, age-matched controls (n = 10). In addition, the levels of 5-hmC in the hippocampus of a pair of monozygotic twins discordant for AD were assessed. The levels of 5-mC and 5-hmC were furthermore analyzed in a cell-type and hippocampal subregion–specific manner, and were correlated with amyloid plaque load and neurofibrillary tangle load. The results showed robust decreases in the hippocampal levels of 5-mC and 5-hmC in AD patients (19.6% and 20.2%, respectively). Similar results were obtained for the twin with AD when compared to the non-demented co-twin. Moreover, levels of 5-mC as well as the levels of 5-hmC showed a significant negative correlation with amyloid plaque load in the hippocampus (r_p = −0.539, p = 0.021 for 5-mC and r_p = −0.558, p = 0.016 for 5-hmC). These human postmortem results thus strengthen the notion that AD is associated with alterations in DNA methylation and hydroxymethylation, and provide a basis for further epigenetic studies identifying the exact genetic loci with aberrant epigenetic signatures.     

Health literacy and coronary artery disease: A systematic review

Objective

Identify health literacy (HL) screening instruments available to CAD patients; describe the prevalence of low HL; explore the predictors of low HL; and, identify the association between HL, health behaviors, and outcomes among these patients.

DNA甲基化在肿瘤诊断和治疗中应用的研究进展

DNA甲基化是重要的表遗传学修饰方式.启动子区异常高甲基化是抑癌基因表达失活的主要机制之一,与肿瘤的发生密切相关.现重点将DNA异常甲基化研究在临床肿瘤诊断、治疗以及监测等方面的应用及意义作一综述.     

Identification of disease-associated DNA methylation in intestinal tissues from patients with inflammatory bowel disease

Lin Z, Hegarty JP, Cappel JA, Yu W, Chen X, Faber P, Wang Y, Kelly AA, Poritz LS, Peterson BZ, Schreiber S, Fan J‐B, Koltun WA. Identification of disease‐associated DNA methylation in intestinal tissues from patients with inflammatory bowel disease. Overwhelming evidence supports the theory that inflammatory bowel disease (IBD) is caused by a complex interplay between genetic predispositions of multiple genes, combined with an abnormal interaction with environmental factors. It is becoming apparent that epigenetic factors can have a significant contribution in the pathogenesis of disease. Changes in the methylation state of IBD‐associated genes could significantly alter levels of gene expression, potentially contributing to disease onset and progression. We have explored the role of DNA methylation in IBD pathogenesis. DNA methylation profiles (1505 CpG sites of 807 genes) of matched diseased (n = 26) and non‐diseased (n = 26) intestinal tissues from 26 patients with IBD [Crohn's disease (CD) n = 9, ulcerative colitis (UC) n = 17] were profiled using the GoldenGate? methylation assay. After an initial identification of a panel of 50 differentially methylated CpG sites from a training set (14 non‐diseased and 14 diseased tissues) and subsequent validation with a testing set (12 non‐diseased and 12 diseased tissues), we identified seven CpG sites that are differentially methylated in intestinal tissues of IBD patients. We have also identified changes in DNA methylation associated with the two major IBD subtypes, CD and UC. This study reports IBD‐associated changes in DNA methylation in intestinal tissue, which may be disease subtype‐specific.