Kagan, J., Srivastava, S., Barker, P. E., Belinsky, S. A. & Cairns, P. Towards clinical application of methylated DNA sequences as cancer biomarkers: a joint NCI's EDRN & NIST workshop on standards, methods, assays, reagents and tools (SMART). Cancer Res. 67, 4545-4549

ArticleinCancer Research 67(10):4545-9 · June 2007with4 Reads
DOI: 10.1158/0008-5472.CAN-06-2888 · Source: PubMed
Abstract
The workshop report, entitled Towards Clinical Application of Methylated DNA Sequences as Cancer Biomarkers: A Joint National Cancer Institute's Early Detection Research Network and National Institute of Standards and Technology Workshop, presents a summary of the main issues, current challenges, outcomes, and recommendations toward application of methylated DNA sequences as cancer biomarkers.
    • "Third, another critical problem remains with regards to the efficiency of DNA extraction, quantification of DNA and efficiency of bisulfite conversion. Collectively, these limitations reinforce the notion that all these challenges must be overcome and DNA methylation detection must be standardized to be permit efficient development of these biomarkers for cancer detection [78] . Guidelines, including universal individual laboratory instructions, should be encouraged for the standardization of methylated DNA analysis in body fluids. "
    [Show abstract] [Hide abstract] ABSTRACT: Cancer initiation and progression is controlled by both genetic and epigenetic events. Epigenetics refers to the study of mechanisms that alter gene expression without permanently altering the DNA sequence. Epigenetic alterations are reversible and heritable, and include changes in histone modifications, DNA methylation, and non-coding RNA-mediated gene silencing. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Aberrant epigenetic modifications occur at the earliest stages of neoplastic transformation and are now believed to be essential players in cancer initiation and progression. Recent advances in epigenetics have not only offered a deeper understanding of the underlying mechanism(s) of carcinogenesis, but have also allowed identification of clinically relevant putative biomarkers for the early detection, disease monitoring, prognosis and risk assessment of cancer patients. At this moment, DNA methylation and non-coding RNA including with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) represent the largest body of available literature on epigenetic biomarkers with the highest potential for cancer diagnosis. Following identification of cell-free nucleic acids in systematic circulation, increasing evidence has demonstrated the potential of cell-free epigenetic biomarkers in the blood or other body fluids for cancer detection. In this article, we summarize the current state of knowledge on epigenetic biomarkers - primarily DNA methylation and non-coding RNAs - as potential substrates for cancer detection in gastric and colorectal cancer, the two most frequent cancers within the gastrointestinal tract. We also discuss the obstacles that have limited the routine use of epigenetic biomarkers in the clinical settings and provide our perspective on approaches that might help overcome these hurdles, so that these biomarkers can be readily developed for clinical management of cancer patients.
    Full-text · Article · Aug 2014
    • "The direct, real-time MSP assay is the current preferred method which yields a quantitative test result by normalizing the copy number of a methylated MGMT promoter to a control gene.[43] Compared with the conventional gel-based assay, the novel test protocol is considered of having higher sensitivity, higher reproducibility and higher efficiency due to the real-time PCR platform4243. A quantitative readout can also allow the determination and investigation of an optimal cutoff point for clinical prediction.[37] "
    [Show abstract] [Hide abstract] ABSTRACT: The clinical implication of O6-methylguanine-DNA methyltransferase (MGMT) promoter status is ill-defined in elderly glioblastoma patients. Here we report a meta-analysis to seek valid evidence for its clinical relevance in this subpopulation. Literature were searched and reviewed in a systematic manner using the PubMed, EMBASE and Cochrane databases. Studies investigating the association between MGMT promoter status and survival data of elderly patients (≥65 years) were eligible for inclusion. Totally 16 studies were identified, with 13 studies included in the final analyses. The aggregate proportion of MGMT promoter methylation in elderly patients was 47% (95% confidence interval [CI]: 42-52%), which was similar to the value for younger patients. The analyses showed differential effects of MGMT status on overall survival (OS) of elderly patients according to assigned treatments: methylated vs. unmethylated: (1) temozolomide (TMZ)-containing therapies: hazard ratio [HR] 0.49, 95% CI 0.41-0.58; (2) TMZ-free therapies: HR 0.97, 95% CI 0.77-1.21. More importantly, a useful predictive value was observed by an interaction analysis: TMZ-containing therapies vs. RT alone: (1) methylated tumors: HR 0.48, 95% CI 0.36-0.65; (2) unmethylated tumors: HR 1.14; 95% CI 0.90-1.44. The meta-analysis reports an age-independent presence of MGMT promoter methylation. More importantly, the study encouraged routine testing of MGMT promoter status especially in elderly glioblastoma patients by indicating a direct linkage between biomarker test and individual treatment decision. Future studies are needed to justify the mandatory testing in younger patients.
    Full-text · Article · Jan 2014
    • "Punturieri et al [31] suggested that lung cancer and COPD might be two sides of the same coin. Because DNA methylation, histone deacetylation, and protein phosphorylation are involved in the pathogenesis of lung cancer323334, it is suggested that epigenetic modifications may also attribute to the pathogenesis of COPD, either alone or when associated with lung cancer [35,36]. Demeo et al [14] found that DNA methylation status at distinct CpG loci was associated with both the presence and severity of COPD and lung function, suggesting that DNA methylation may be a biomarker of COPD and may highlight new pathways of COPD pathogenesis. "
    [Show abstract] [Hide abstract] ABSTRACT: Apoptosis plays a central role in the pathogenesis of chronic obstructive pulmonary disease (COPD), and this process can be regulated by mitochondrial transcription factor A (mtTFA). Epigenetics is involved in the regulation and modification of the genes involved in lung cancer and COPD. In this study, we determined the expression of mtTFA and its methylation levels in the COPD patients with lung cancer. Twenty-one squamous cell lung cancer patients, 11 with COPD and 10 without COPD, undergoing pneumonectomy were enrolled. The apoptotic index (AI) of pulmonary vascular endothelial cells was analyzed by transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay. The expression of mtTFA mRNA and protein was measured using PCR, immunohistochemistry and Western-blot. Methylation of the mtTFA promoter was detected using bisulfite sequencing PCR. Compared to the non-COPD group, the AI was higher, and expression of mtTFA mRNA and protein was lower in the COPD group (P<0.001). Expression of the mtTFA protein was positively correlated with FEV1/Pre (r = 0.892, P<0.001), and negatively correlated with AI (r = -0.749, P<0.001) and smoke index (r = -0.763, P<0.001). Percentage of mtTFA promoter methylation in the COPD patients was significantly higher compared to the non-COPD patients (P<0.05). These results suggest that the expression of mtTFA mRNA and protein is down-regulated in the lung tissue from the COPD patients with squamous cell lung cancer, and the level of mtTFA protein is related to apoptosis of pulmonary vascular endothelial cells. Aberrant mtTFA methylation may also play an important role in the pathogenesis of COPD.
    Full-text · Article · Dec 2013
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