胃癌前病变中DNA甲基化状态与叶酸

DNA甲基化异常是胃癌发生的重要机制之一,为了能尽早发现并纠正DNA甲基化异常,阻止胃癌的发生,胃黏膜癌前病变中DNA甲基化状态的研究日益受到重视．众多研究表明,胃黏膜癌前病变中多种基因中存在甲基化异常,而且基因的甲基化异常程度与年龄、性别有关,还与胃黏膜上皮细胞是否存在活动性炎症、肠化及幽门螺杆菌感染有关．叶酸缺乏可导致DNA甲基化的紊乱和DNA修复机制效率的减弱, 叶酸摄入量不足患胃癌的相对危险度增高;胃黏膜癌前病变患者体内叶酸不足,黏膜细胞总基因组DNA甲基化水平下降;经叶酸治疗后,体内叶酸升高,黏膜细胞总基因组DNA 甲基化水平上升,异型增生、肠上皮化生明显改善．因此,叶酸缺乏与胃黏膜癌前病变的发生、发展有关,及时纠正叶酸不足,可逆转胃黏膜的病理改变,减少胃癌的发生．     

DNA低甲基化与肿瘤的关系

DNA甲基化异常包括全基因组的低甲基化和局部基因的高甲基化。在肿瘤的发生、发展过程中,DNA低甲基化比高甲基化更为常见。DNA甲基化且与肿瘤类型、肿瘤分期及肿瘤侵袭的顺序中表现出相当的特异性。DNA低甲基化对肿瘤的早期诊断和预防有重要意义。     

胃癌的化学预防

当前对胃癌化学预防的研究主要集中在根除幽门螺杆菌(H.pylori)﹑抗氧化剂﹑叶酸、选择性环氧合酶(COX)-2抑制剂上。动物实验和临床研究均发现,根除H.pylori能够预防胃癌的发生,在癌前病变形成前根除效果更佳。某些抗氧化剂(β-胡萝卜素、维生素A、C、E,绿茶、硒等)和叶酸通过保护DNA免受氧化损害和提高DNA甲基化水平预防胃癌的发生。选择性COX-2抑制剂在动物实验中能显著降低胃癌发生率和癌前病变发生率,目前已正式用于肿瘤的预防,其预防效果有待于大规模临床研究。     

胰腺癌DNA甲基化谱研究进展

肿瘤的发生与多基因的异常有关.其中DNA甲基化作为基因表达调控的一种方式,与基因的异常表达相关,从而影响肿瘤的生物学特性.本文就对胰腺癌有关基因的CpG岛甲基化情况做一综述,阐述DNA甲基化与胰腺癌发生的关系.     

DNA甲基化在结直肠癌及癌前病变早期诊断中的研究进展

结直肠癌预后取决于诊断时的肿瘤分期, 因此早诊早治显得尤为重要, 目前应用较多的结直肠癌筛查手段存在不同程度的局限性。在结直肠癌的发展过程中伴随DNA异常甲基化, DNA甲基化检测特别是多基因联合检测在相关研究中显示出不俗的筛查潜力, 有望成为结直肠癌早期筛查的新型无创检测手段。本文综述了DNA甲基化在结直肠癌及其癌前病变早期筛查中的研究进展。     

胰腺癌DNA甲基化谱研究进展

肿瘤的发生与多基因的异常有关。其中DNA甲基化作为基因表达调控的一种方式,与基因的异常表达相关,从而影响肿瘤的生物学特性。本文就对胰腺癌有关基因的CpG岛甲基化情况做一综述,阐述DNA甲基化与胰腺癌发生的关系。一、与胰腺癌相关的基因甲基化1.p16基因:p16基因属于INK4a/AR     

DNA甲基化与结肠癌

DNA异常甲基化是肿瘤常见的表观遗传学改变.广泛的低甲基化和区域性高甲基化是基因异常表达的常见机制.某些基因异常甲基化与结肠癌发生密切相关,且常见于结肠癌发病早期.     

DNA甲基化与垂体肿瘤

DNA甲基化是肿瘤抑制基因的失活方式之一 ,它能导致与细胞增殖及分化的相关基因表达异常 ,造成细胞恶变形成肿瘤 ,特别是p1 6基因 ,在垂体肿瘤中的甲基化发生率高达 70 %～ 80 % ,说明DNA甲基化在垂体肿瘤的发生发展过程中起重要作用 ,本文重点对垂体肿瘤发生过程的DNA甲基化过程及p1 6基因失活机制研究进展进行综述。     

DNA甲基化水平降低与消化系肿瘤

研究表明DNA甲基化(DNA methylation)是维持细胞遗传稳定性的一个重要因素。环境及营养因素可引起DNA甲基化水平降低,影响RNA转录,导致癌基因表达,因而与肿瘤特别是消化系肿瘤的发生有关。本文综述了DNA甲基化的生物学意义、其水平降低与消化系肿瘤的关系,以有助于加深对消化系肿瘤发病机制中分子生物学方面的认识。     

地西他滨在造血干细胞移植中的应用

DNA高度甲基化在恶性血液病中普遍存在,与其发病密切相关.特别是髓系肿瘤中,多个组蛋白甲基化相关调节酶的表达异常与髓系肿瘤的发生、发展密切相关[1],因此具有调节甲基化的药物,如地西他滨、阿扎胞苷具有广泛的抗肿瘤作用[2].     

胃癌癌前病变的研究进展及防治对策

胃癌癌前病变(precancerous lesions of gastric cancer,PLGC)是胃癌发生和发展过程中的一个重要阶段,早期发现和干预是防控胃癌的重要手段.在PLGC的形成过程中,DNA甲基化、微卫星不稳定性、p53以及幽门螺杆菌(Helicobacter pylori,H.pylori)感染等占有重要位置.鉴于胃癌的高度恶性,且其病因发病机制尚未完全阐明,实施针对病因的一级预防比较困难.本文就目前PLGC发病机制、防治对策等问题进行总结,以便于临床医师对胃癌前病变进行密切的监测及有效的干预.     

Differential methylation landscape of pancreatic ductal adenocarcinoma and its precancerous lesions

Background: Pancreatic cancer is one of the most lethal diseases with an incidence almost equal to the mortality. In addition to having genetic causes, cancer can also be considered an epigenetic disease. DNA methylation is the premier epigenetic modification and patterns of aberrant DNA methylation are recognized to be a common hallmark of human tumor. In the multistage carcinogenesis of pancreas starting from precancerous lesions to pancreatic ductal adenocarcinoma(PDAC), the epigenetic changes play a significant role. Data sources: Relevant studies for this review were derived via an extensive literature search in Pub Med via using various keywords such as pancreatic ductal adenocarcinoma, precancerous lesions, methylation profile, epigenetic biomarkers that are relevant directly or closely associated with the concerned area of our interest. The literature search was intensively done considering a time frame of 20 years(1998–2018). Result: In this review we have highlighted the hypermethylation and hypomethylation of the precancerous PDAC lesions(pancreatic intra-epithelial neoplasia, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm and chronic pancreatitis) and PDAC along with the potential biomarkers. We have also achieved the early epigenetic driver that leads to progression from precancerous lesions to PDAC. A bunch of epigenetic driver genes leads to progression of precancerous lesions to PDAC( pp ENK, APC, p14/5/16/17, h MLH1 and MGMT) are also documented. We summarized the importance of these observations in therapeutics and diagnosis of PDAC hence identifying the potential use of epigenetic biomarkers in epigenetic targeted therapy. Epigenetic inactivation occurs by hypermethylation of Cp G islands in the promoter regions of tumor suppressor genes. We listed all hyper-and hypomethylation of Cp G islands of several genes in PDAC including its precancerous lesions. Conclusions: The concept of the review would help to understand their biological effects, and to determine whether they may be successfully combined with other epigenetic drugs. However, we need to continue our research to develop more specific DNA-demethylating agents, which are the targets for hypermethylated Cp G methylation sites.     

DNA methylation,smooth muscle cells,and atherogenesis

DNA methylation is a form of epigenetic modification of the genome that can regulate gene expression. Hypermethylation of CpG islands in the promoter areas leads to decreased gene expression, whereas promoters of actively transcribed genes remain nonmethylated. Because of cellular proliferation and monoclonality of at least some of the lesion cells, atherosclerotic lesions have been compared with benign vascular tumors.1,2 However, although genetic and epigenetic background favors neoplastic transformation, atherosclerotic plaques never develop to malignant tumors. Among cancer cells, common features are genome-wide hypomethylation, which correlates with transformation and tumor progression. Recent studies have shown that DNA methylation changes occur also during atherogenesis and may contribute to the lesion development.     

人粪便SFRP2基因甲基化分析对结直肠癌的诊断价值

目的探讨人粪便中分泌型卷曲相关蛋白2(SFRP2)基因甲基化分析用于结直肠癌(CRC)早期诊断的可行性。方法从87例结直肠癌或良性病变的患者及24例正常对照者的粪便中分别提取DNA,采用甲基化特异性PCR(MSP)技术分析其SFRP2基因甲基化状态。结果CRC、腺瘤、增生性息肉和溃疡性结肠炎患者的SFRP2基因甲基化阳性率分别为94.2%(49/52)、52.4%(11/21)、37.5%(3/8)和16.7%(1/6)。1例正常对照SFRP2基因甲基化检测阳性。检测SFRP2基因甲基化诊断CRC及癌前病变的敏感性和特异性分别为90.5%和85.4%。结论SFRP2基因甲基化是CRC进展过程中的早期事件。粪便SFRP2基因甲基化分析可望成为CRC早期无创诊断或CRC高风险人群筛查的新途径。     

肝细胞癌癌前病变的诊断和治疗多学科专家共识(2020版)

肝癌目前占我国癌症死因的第二位。我国肝癌的发病特点大多遵循乙型肝炎-肝硬化-肝癌的"三步曲"模式。癌前病变的筛查在胃癌、大肠癌和宫颈癌等恶性肿瘤的诊治中已取得了显著的成果。肝硬化状态下的不典型增生结节具有较强的恶变潜能,尤其是高级别不典型增生结节癌变率极高。基于国内外在这一领域的研究成果和专家临床经验,《肝细胞癌癌前病变的诊断和治疗多学科专家共识(2020版草案)》经多学科协作对肝脏高级别不典型增生结节作为肝癌的癌前病变,从概念、筛查、诊断、治疗和随访等各方面进行了归纳和界定,旨在提出和建立肝癌癌前病变的概念和诊疗原则,为降低我国肝癌的发病率和提高肝癌的总体治疗效果作出贡献。     

肝细胞癌癌前病变的诊断和治疗多学科专家共识( 2020版)

肝癌目前占我国癌症死因的第二位。我国肝癌的发病特点大多遵循乙型肝炎-肝硬化-肝癌的“三步曲”模式。癌前病变的筛查在胃癌、大肠癌和宫颈癌等恶性肿瘤的诊治中已取得了显著的成果。肝硬化状态下的不典型增生结节具有较强的恶变潜能,尤其是高级别不典型增生结节癌变率极高。基于国内外在这一领域的研究成果和专家临床经验,《肝细胞癌癌前病变的诊断和治疗多学科专家共识(2020版)》经多学科协作对肝脏高级别不典型增生结节作为肝癌的癌前病变,从概念、筛查、诊断、治疗和随访等各方面进行了归纳和界定,旨在提出和建立肝癌癌前病变的概念和诊疗原则,为降低我国肝癌的发病率和提高肝癌的总体治疗效果作出贡献。     

Promoter hypomethylation of protease-activated receptor 2 associated with carcinogenesis in the stomach

BACKGROUND AND AIM: Trypsin acting at protease-activated receptor 2 (PAR2) contributes to a progression of malignant tumors. An abnormal DNA methylation has been recognized as an important molecular mechanism for the genesis of various types of cancers. We attempted to clarify the relationship between the promoter methylation of PAR2 and gastric cancer. METHOD: We estimated the methylation of the PAR2 promoter in both antral non-cancerous mucosa and cancer lesions in 94 patients with gastric cancer. We employed a methylation-specific PCR method. RESULTS: Regarding the methylation ratio (MR) of antral-non-cancerous mucosa, no significant difference was despite among gender, age and Helicobacter pylori infection status, whereas MR increased rising inflammation scores. The MR of cancer lesions was significantly lower than that of antral non-cancerous mucosa. This finding was not dependent on tumor staging, but also histological classification. In venous invasion, lymph node metastasis, or peritoneal dissemination negative cases, this significant lower MR was also seen. CONCLUSION: The promoter methylation of PAR2 seems to be increased with a progression of chronic inflammation and has an inhibitory effect on carcinogenesis of the stomach.     

Local hypomethylation in atherosclerosis found in rabbit ec-sod gene.

Extracellular superoxide dismutase (EC-SOD) protects arteries against deleterious effects of superoxide anions and the development of atherosclerosis. In this study, we cloned and characterized rabbit ec-sod gene. We identified 6 rabbit C-elements and 5 CpG clusters in the cloned sequence. One of the CpG clusters is located on the coding sequence. Because CpG clusters are potential sites for methylation and may explain the occurrence of mutations, methylation status of each of the CpG dimers located in the coding sequence CpG cluster was characterized using direct genomic sequencing. Unexpectedly, a marked reduction in the amount of methylated CpG dinucleotides in ec-sod gene was detected in atherosclerotic aortas as compared with normal aortic intima-media. Although alterations in DNA methylation are well characterized in malignant tumors, the presence of methylation changes in atherosclerosis has not been studied even though both diseases are characterized by excess cellular proliferation and alterations in gene expression. Further analysis of the whole genomic methylation by high-pressure liquid chromatography in normal and atherosclerotic aortas revealed a tendency for a decreased 5-methylcytosine (5-mC) content in atherosclerotic aortas as compared with normal arteries. Hypomethylation in atherosclerotic aortas occurred at the same level as has been reported from malignant tumors. Although a causal relationship between the methylation level and expression of EC-SOD cannot be proven, our results show that ec-sod hypomethylation is associated with the development of atherosclerosis and suggest that it may affect structure and function of ec-sod and other genes possibly involved in the development of atherosclerotic lesions.     

Hypermethylation of <Emphasis Type="Italic">SFRP2</Emphasis> as a Potential Marker for Stool-Based Detection of Colorectal Cancer and Precancerous Lesions

DNA methylation is a key mechanism of colorectal carcinogenesis. Analysis of aberrantly methylation in stool DNA might provide a novel strategy for noninvasive detection of colorectal cancer (CRC). To explore the feasibility of this approach, we have assessed the methylation status of secreted frizzled-related protein gene 2 (SFRP2) in stool samples from patients with CRC with respect to a series of healthy individuals and patients with benign colorectal diseases, using methylation-specific polymerase chain reaction. Methylated SFRP2 occurs in 94.2%, 52.4%, 37.5%, and 16.7% of patients with CRC, adenomas, hyperplstic polyps, and ulcerative colitis, respectively. Of the 24 normal individuals, only 1 revealed methylated DNA. The pilot study revealed that aberrant methylated SFRP2 could be detected frequently in stools from patients with CRC and precancerous lesions. Methylation testing of fecal DNA may be a simple, promising, and noninvasive screening tool for colorectal neoplasia.