基于血液DNA甲基化在肝癌诊断中的研究进展

肝癌是世界范围内致死率最高的癌症之一,早期诊断率低,通常在发现肝癌时患者已经处于晚期。早期诊断是降低肝癌患者死亡率的重要手段,但目前尚无诊断肝癌的可靠血液学分子标志物。循环游离DNA甲基化检测是诊断肿瘤的一种潜在的非侵入式方法。本文结合循环游离DNA甲基化在肝癌诊断中的最新研究,主要综述血液中单个DNA甲基化标志物、多个DNA甲基化标志物联合及DNA甲基化标志物联合甲胎蛋白(AFP)在肝癌诊断方面的研究进展。     

Emerging stool-based and blood-based non-invasive DNA tests for colorectal cancer screening: the importance of cancer prevention in addition to cancer detection

Colorectal cancer (CRC) screening can be undertaken utilizing a variety of distinct approaches, which provides both opportunities and confusion. Traditionally, there has often been a trade-off between the degree of invasiveness of a screening test and its ability to prevent cancer, with fecal occult blood testing (FOBT) and optical colonoscopy (OC) at each end of the spectrum. CT colonography (CTC), although currently underutilized for CRC screening, represents an exception since it is only minimally invasive, yet provides accurate evaluation for advanced adenomas. More recently, the FDA approved a multi-target stool DNA test (Cologuard) and a blood-based test (Epi proColon) for average-risk CRC screening. This commentary will provide an overview of these two new non-invasive tests, including the clinical indications, mechanism of action, and diagnostic performance. Relevance to radiology practice, including a comparison with CTC, will also be discussed.     

Application of DNA methylation biomarkers for endometrial cancer management

It has become clear that aberrant gene expression, via alterations in promoter methylation or histone acetylation, is a contributing factor for carcinogenesis, perhaps as important as genetic mutation. This is particularly evident in endometrial cancer, in which multiple genes are silenced through hypermethylation. In this review, we discuss the field of epigenetics and relevant techniques to characterize methylation and acetylation alterations. The CpG island methylator phenotype, epimutations and the effects of aging on methylation are also discussed. In endometrial cancer there is evidence that hypermethylation of relevant genes can be reversed using epigenetic inhibitors, resulting in re-expression of silenced genes. Preliminary data also suggest that a panel of methylation biomarkers could be useful for diagnosis and even screening in selected populations at high risk. This disease is particularly well suited for such a strategy given that the endometrium is readily accessible for testing and endometrial cancer precursors are well defined.     

DNA methylation detection methods used in colorectal cancer

Colorectal cancer (CRC) remains a major contributor to the number of cancer-related deaths that occur annually worldwide. With the development of molecular biology methods, an increasing number of molecular biomarkers have been identified and investigated. CRC is believed to result from an accumulation of epigenetic changes, and detecting aberrant DNA methylation patterns is useful for both the early diagnosis and prognosis of CRC. Numerous studies are focusing on the development of DNA methylation detection methods or DNA methylation panels. Thus, this review will discuss the commonly used techniques and technologies to evaluate DNA methylation, their merits and deficiencies as well as the prospects for new methods.     

DNA methylation biomarkers in cancer: progress towards clinical implementation

Altered DNA methylation is ubiquitous in human cancers and specific methylation changes are often correlated with clinical features. DNA methylation biomarkers, which use those specific methylation changes, provide a range of opportunities for early detection, diagnosis, prognosis, therapeutic stratification and post-therapeutic monitoring. Here we review current approaches to developing and applying DNA methylation biomarkers in cancer therapy. We discuss the obstacles that have so far limited the routine use of DNA methylation biomarkers in clinical settings and describe ways in which these obstacles can be overcome. Finally, we summarize the current state of clinical implementation for some of the most widely studied and well-validated DNA methylation biomarkers, including SEPT9, VIM, SHOX2, PITX2 and MGMT.     

Polyunsaturated fatty acids and DNA methylation in colorectal cancer

Colorectal cancer (CRC) has been designated a major global problem, especially due to its high prevalence in developed countries. CRC mostly occurs sporadically (75%-80%), and only 20%-25% of patients have a family history. Several processes are involved in the development of CRC such as a combination of genetic and epigenetic alterations. Epigenetic changes, including DNA methylation play a vital role in the progression of CRC. Complex interactions between susceptibility genes and environmental factors, such as a diet and sedentary lifestyle, lead to the development of CRC. Clinical and experimental studies have confirmed the beneficial effects of dietary polyunsaturated fatty acids (PUFAs) in preventing CRC. From a mechanistic viewpoint, it has been suggested that PUFAs are pleiotropic agents that alter chromatin remodeling, membrane structure and downstream cell signaling. Moreover, PUFAs can alter the epigenome via modulation of DNA methylation. In this review, we summarize recent investigations linking PUFAs and DNA methylation-associated CRC risk.     

A novel multitarget stool DNA test for colorectal cancer screening

Review of: Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, Ahlquist DA, Berger BM. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med 2014;370(14):1287–97.

This Practice Pearl reviews the results of a prospective, multicenter, cross-sectional clinical study that evaluated the performance of a new multitarget stool DNA (or mt-sDNA) screening test for colorectal cancer (CRC) and compared it with a fecal immunochemical test (FIT) in individuals at average risk for CRC. The potential impact of this test on the future of CRC screening is also discussed in a brief commentary. mt-sDNA testing is a noninvasive screening test designed to detect DNA biomarkers associated with colorectal neoplasia and occult hemoglobin in the stool. The sensitivity of mt-sDNA testing for detection of CRC was 92.3%, compared with 73.8% for FIT (p = 0.002). Sensitivity for detecting advanced precancerous lesions was 42.4% for mt-sDNA testing and 23.8% for FIT (p < 0.001). The specificities of mt-sDNA testing and FIT were 86.6% and 94.9%, respectively (p < 0.001). mt-sDNA testing thus may be a first-line screening option for asymptomatic individuals at average risk for CRC who do not want to have a colonoscopy.     

Gut microbiome: New biomarkers in early screening of colorectal cancer

BackgroundCertain “star intestinal bacteria” have been found to act as a contributor to the development of colorectal cancer (CRC). Besides, given that the gut microbiome can be detected in a diverse range of samples (stool, tissue, blood, etc), it is categorized into fecal microbiome, blood microbiome, and tissue microbiome.MethodsTo provide an overview of the recent research progress, this review summarizes the characteristics of the gut microbiome in different samples at each stage of CRC and their screening efficiency.ResultsThe screening models constructed from different sample microbiomes (healthy/colorectal adenoma, healthy/CRC, and colorectal adenoma/CRC) have both strengths and constraints in terms of biomarker reproducibility and area under the receiver‐operating characteristic curve (AUC) of the screening models. Many bacteria, such as Bifidobacteria, Fusobacterium nucleatum (F. n), Geotrichum candidum, Porphyromonas asaccharolytica, Escherichia coli, Rhodococcus, Anaerostipes caccae, Enhydrobacter, Lachnoclostridiumsp. m3, Bacteroides clarus, Clostridium hathewayi, Ruminococcaceae, Bacteroides thetaiotaomicron, Culinariside, and enterotoxigenic Bacteroides fragilis (ETBF), show favorable diagnostic efficacy in early screening of colorectal cancer.ConclusionsThis review highlights stool, blood, tissue, and bowel fluid are the main sample sources for biomarkers, each with its own advantages and limitations. Moreover, other samples such as extracellular vesicles and biofilms also should been deserved further attention.     

粪便DNA甲基化分析在结直肠癌诊断中的应用价值

目的研究人粪便中分泌型卷曲相关蛋白2（SFRP2）、增生性息肉蛋白（HPPI）和O^6．甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因甲基化状态及其用于结直肠癌（CRC）筛查的可行性。方法从52例CRC患者、35例结直肠良性疾病患者和24名正常对照者粪便标本中提取DNA，采用甲基化特异性PCR（MSP）技术分析粪便DNA中SFRP2、HPPI和MGMT基因甲基化状态。结果CRC患者粪便SFRF2、HPP1和MGMT基因甲基化阳性率分别为94．2％、71．2％和48．1％;96.2％的CRC和81．8％的癌前病变患者中至少存在1个基因的过甲基化。1例正常粪便标本SFRP2甲基化阳性。联合3个基因诊断CRC和癌前病变的敏感度、特异度、阳性预测值和阴性预测值分别为93．7％、77．1％、84．3％和90．2％。结论联合分析SFRP2、HPP1和MGMT基因甲基化是检测CRC及癌前病变的高敏感性方法。检测粪便基因甲基化有望成为CRC无创诊断或高风险人群筛查的一个新途径。     

Circulating cell-free nucleic acids as biomarkers in colorectal cancer screening and diagnosis

Screening methods for the most frequent diagnosed malignant tumor, colorectal cancer (CRC), have limitations. Circulating cell-free DNA (cfDNA) analysis came into focus as a potential screening test for CRC. Detection of epigenetic and genetic alterations of cfDNA as DNA methylation or DNA mutations and related ribonucleic acids may improve cancer detection based on unique, CRC-specific patterns. In this review the authors summarize the CRC-specific nucleic acid biomarkers measured in peripheral blood and their potential as screening markers. Detection of DNA mutation has inadequate sensitivity; however, methylated DNA can be established with higher sensitivity from CRC plasma samples. The ribonucleic acid based miRNA studies represented higher sensitivity for CRC as compared with mRNA studies. Recently, isolation of cfDNA has become automated, highly reproducible and a high throughput method. With automated possible diagnostic tools, a new approach may be available for CRC screening as liquid biopsy.     

血浆游离DNA甲基化靶向测序在结直肠癌中的应用价值

目的 检测结直肠癌(CRC)患者血浆游离DNA(cell-free DNA,cfDNA)的甲基化水平,并分析其临床应用价值.方法 收集38例大连大学附属新华医院就诊的CRC患者(Ⅰ～Ⅲ期)及38例体检健康者的血液标本,采用化学发光法检测血清癌胚抗原(CEA)水平;提取CRC组及体检健康者血浆cfDNA,行高通量甲基化靶...     

Assessment and screening for colorectal cancer

Despite the reduction of and improvement in the survival rates for colon and rectum (colorectal) cancer, this form of cancer remains one of the most prevalent malignancies in the United States. More than 90% of colorectal cancer cases occur in people older than 50, the typical age group of home care provider clients. Educating these clients about the symptoms, screening methods, and treatments for colorectal cancer should be a routine part of the care provided by home health providers.     

Barriers to screening for colorectal cancer

Rapidly growing interest in colon cancer screening is a crucial first step to identifying and reducing many of the barriers that impede population screening for this common disease. Promoting screening demands health care policy change to increase the percentage of Americans with insurance coverage that includes a colon cancer screening benefit. A systematic approach to screening with invitations that come from a clinician are likely to be the most effective way to prompt more individuals to be screened. Awareness campaigns and patient educational aids, including decision tools, implemented in multiple sites, such as worksites, community centers, health care systems, and physician offices, increase the percent of eligible Americans who understand their personal risk, the need for screening, and the options available to them.     

Aberrant methylation of genes in stool samples as diagnostic biomarkers for colorectal cancer or adenomas: a meta-analysis

Background: An increasing number of hypermethylated genes in stool samples have been reported as biomarkers for the detection of colorectal cancer (CRC) or adenomas. We aimed to comprehensively review and compare the evidence for feasibility of using these biomarkers for the detection of colorectal neoplasia. Methods: We searched Medline, the Web of Science and OVID for studies that used hypermethylated genes as biomarkers for the detection of CRC or adenomas. A meta‐analysis was carried out using the random‐effect model with diagnostic odd ratios (DOR) and 95% confidence intervals (CI) as effect measurements. Results: A total of 19 studies including 2,356 patients were eligible for final analysis. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and DOR for the detection of CRC or adenomas were 0.62 (95% CI: 0.51–0.71), 0.89 (95% CI: 0.86–0.92), 5.66 (95% CI: 4.68–6.83), 0.43 (95% CI: 0.34–0.55) and 13.15 (95% CI: 9.82–17.60) respectively. Of these, the sensitivity and specificity for the detection of adenoma were 0.54 (95% CI: 0.39–0.68) and 0.88 (95% CI: 0.83–0.92) respectively. Conclusions: Hypermethylated gene panels are not currently accurate enough to be used alone for colorectal neoplasia screening. The discovery and evaluation of additional biomarkers with improved sensitivity and specificity is necessary.     

Epigenetic biomarkers in colorectal cancer diagnostics

Colorectal cancer (CRC) is a significant health burden worldwide. Despite advancements in treatment options, improvements in CRC patient survival have been limited owing to lack of early detection and limited capacity for optimal therapeutic decision-making. Biomarkers to improve CRC diagnosis, prognosis and prediction of treatment response therefore represent opportunities to improve patient outcome. In addition to genetic alterations and genomic instability, it is now clear that epigenetic alterations play dramatic roles in driving tumor onset and progression in CRC. A recent surge in investigation of epigenetic biomarkers including DNA methylation, miRNA expression and histone modifications has demonstrated that these alterations may be enticing translational biomarker candidates in CRC. In particular, methylation kits have already been incorporated into clinical practice for a handful of cancers, including CRC. This review will aim to summarize the established and emerging roles of epigenetic modifications in CRC detection, prognostication and prediction of treatment response.     

粪便SDC2基因甲基化检测联合结肠镜在早期结直肠癌筛查中的意义

目的探讨粪便SDC2基因甲基化检测联合结肠镜在早期结直肠癌(CRC)筛查中的意义。方法选择2018年1月-2019年10月在深圳市宝安区中心医院体检的1 000例体检者作为研究对象,使用试剂盒分别检测粪便SDC2基因甲基化和血浆SEPT9基因甲基化,对两者任一结果为阳性者再行结肠镜检查。比较SDC2和SEPT9基因甲基化检测的阳性率以及两者联合结肠镜对进展性腺瘤和CRC的检出率。结果在1 000例筛查对象中,粪便SDC2基因甲基化检测阳性率明显高于血浆SEPT9基因甲基化〔18.10%(181/1 000)比9.80%(98/1 000)〕,差异有统计学意义(P<0.05);粪便SDC2基因甲基化检测联合结肠镜对进展性腺瘤和CRC的检出率均明显高于血浆SEPT9基因甲基化检测联合结肠镜筛查〔进展性腺瘤检出率:2.50%(25/1 000)比1.00%(10/1 000),CRC检出率:1.50%(15/1 000)比0.50%(5/1 000)〕,差异均有统计学意义(均P<0.05)。结论粪便SDC2基因甲基化检测是一种简单无创的CRC筛查新技术,患者接受程度更高,能够避免大规模肠镜筛查带来的弊端,联合结肠镜检测可作为CRC早期筛查的首选策略。     

Tests and investigations for colorectal cancer screening

Worldwide, colorectal (CRC) is the third most common form of cancer, after lung and breast cancer, and the fourth most common cause of cancer death, although in developed countries CRC incidence is higher and it accounts for an even higher proportion of cancer deaths. Successful treatment of early-stage CRC confers substantial survival advantage, and there is now overwhelming evidence that screening average-risk individuals for CRC reduces the incidence and disease-specific mortality. In spite of considerable research for new biomarkers for CRC, the detection of blood in faeces remains the most effective screening tool. The best evidence to date for population-based CRC screening comes from randomised-controlled trials that used a guaiac-based faecal occult blood test (gFOBt) as the first-line screening modality, whereby test-positive individuals are referred for follow-up investigations, usually colonoscopy. A major innovation in the last ten years or so has been the development of other more analytically sensitive and specific screening techniques for blood in faeces. The faecal immunochemical test for haemoglobin (FIT) confers substantial benefits over gFOBt in terms of analytical sensitivity, specificity and practicality and FIT are now recommended for CRC screening by the European guidelines for quality assurance in colorectal cancer screening and diagnosis. The challenge internationally is to develop high quality CRC screening programmes for which uptake is high. This is especially important for developing countries witnessing an increase in the incidence of CRC as populations adopt more westernised lifestyles.This review describes the tests available for CRC screening and how they are being used worldwide. The reader will gain an understanding of developments in CRC screening and issues that arise in choosing the most appropriate screening test (or tests) for organised population-based screening internationally and optimising the performance of the chosen test (or tests). Whilst a wide range of literature has been cited, this is not a systematic review. The authors provide FOBT CRC screening for a population of 14.6 million in the south of England and the senior author (SPH) was the lead author of the European guidelines for quality assurance in colorectal cancer screening and diagnosis and leads the World Endoscopy Organization Colorectal Cancer Committee’s Expert Working Group on ‘FIT for Screening’.     

Imaging procedures in screening for colorectal cancer

This article is a commentary on the preceding article by F. M. Mendelson et al.