Methylation of TFPI2 in Stool DNA: A Potential Novel Biomarker for the Detection of Colorectal Cancer

Departments of Surgery, Oncology, and Pathology, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Cancer Research (Impact Factor: 9.33). 06/2009; 69(11):4691-9. DOI: 10.1158/0008-5472.CAN-08-0142
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We have used a gene expression array-based strategy to identify the methylation of tissue factor pathway inhibitor 2 (TFPI2), a potential tumor suppressor gene, as a frequent event in human colorectal cancers (CRC). TFPI2 belongs to the recently described group of embryonic cell Polycomb group (PcG)-marked genes that may be predisposed to aberrant DNA methylation in early stages of colorectal carcinogenesis. Aberrant methylation of TFPI2 was detected in almost all CRC adenomas (97%, n = 56) and stages I to IV CRCs (99%, n = 115). We further explored the potential of TFPI2 as a biomarker for the early detection of CRC using stool DNA-based assays in patients with nonmetastatic CRC and average-risk noncancer controls who were candidates for screening. TFPI2 methylation was detected in stool DNA from stage I to III CRC patients with a sensitivity of 76% to 89% and a specificity of 79% to 93%. Detection of TFPI2 methylation in stool DNA may act as a useful adjunct to the noninvasive strategies for screening of CRCs in the future.

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Available from: Nita Ahuja, Oct 04, 2015
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    • "The methylation in the stool of several others markers was proposed as potential marker for CRC screening as single marker, TFPI2 with sensitivity of 68% and specificity of 100% in the cohort of 80 patients and 30 healthy controls (Zhang et al., 2012), P16 with specificity of 20% and a specificity of 100% (Abbaszadegan et al., 2007), Fibrillin-1 with sensitivity of 72% and specificity of 93% (Guo et al., 2013), TFPI2 with sensitivity of 76% to 89% and a specificity of 79–93% (Glockner et al., 2009), NDRG4 in the training set yielded a sensitivity of 61%, and a specificity of 93% and in an independent test set of patients the methylation of this gene yielded a sensitivity of 53% and a specificity of 100% (Melotte et al., 2009), the paraplegia-20 was found with a sensitivity and specificity of 80.2 and 100%, respectively (Zhang et al., 2013a). "
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    ABSTRACT: Cell-free nucleic acids (CFNA) have been reported by several authors in blood, stool, and urine of patients with colorectal cancer (CRC). These genetic biomarkers can be an indication of neoplastic colorectal epithelial cells, and can thus potentially be used as noninvasive tests for the detection of the disease in CRC patients and monitor their staging, without the need to use heavier and invasive tools. In a number of test-trials, these genetic tests have shown the advantage of non-invasiveness, making them well accepted by most of the patients, without major side effects. They have also shown a promising sensitivity and specificity in the detection of malignant and premalignant neoplasms. Moreover, costs for performing such tests are very low. Several studies reported and confirmed the proof of the principle for these genetic tests for screening, diagnosis, and prognosis; the main challenge of translating this approach from research to clinical laboratory is the validation from large and long-term randomized trials to prove sustainable high sensitivity and specificity. In this paper, we present a review on the noninvasive genetics biomarkers for CRC detection described in the literature and the challenges that can be encountered for validation processes.
    Frontiers in Genetics 08/2014; 5:182. DOI:10.3389/fgene.2014.00182
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    • "Cancer genetics and epigenetics have long been considered two separate mechanisms but nowadays it is generally accepted that both act together and take advantage of each other [34]. DNA methylation can be detected and quantified by numerous technologies including genome-wide screening methods as well as locus-or gene-specific high-resolution analysis in different tissue samples and body fluids [43] [44] [45] [46] obtained through non-invasive procedures making DNA methylation a very suitable biomarker. O 6 -methylguanine methyltransferase (MGMT) methylation (to predict treatment response in glioblastoma) and glutathione S-transferase P1 (GSTP1) methylation (to detect prostate cancer) are two examples of promising epigenetic biomarkers proving the applicability of DNA methylation as a biomarker [47] [48] [49] [50]. "
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    ABSTRACT: Radiotherapy is an important component of anti-cancer treatment. However, not all cancer patients respond to radiotherapy, and with current knowledge clinicians are unable to predict which patients are at high risk of recurrence after radiotherapy. There is therefore an urgent need for biomarkers to guide clinical decision-making. Although the importance of epigenetic alterations is widely accepted, their application as biomarkers in radiotherapy has not been studied extensively. In addition, it has been suggested that radiotherapy itself introduces epigenetic alterations. As epigenetic alterations can potentially be reversed by drug treatment, they are interesting candidate targets for anticancer therapy or radiotherapy sensitizers. The application of demethylating drugs or histone deacetylase inhibitors to sensitize patients for radiotherapy has been studied in vitro, in vivo as well as in clinical trials with promising results. This review describes the current knowledge on epigenetics in radiotherapy.
    Radiotherapy and Oncology 05/2014; 111(2). DOI:10.1016/j.radonc.2014.05.001 · 4.36 Impact Factor
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    • "In breast cancer patients, the patterns of methylation of the ESR1 and 14-3-3-σ promoters were significantly different compared to healthy controls (28). Glockner et al (29) reported that methylation of the tissue factor pathway inhibitor 2 gene was frequently detected in 171 samples from human colorectal cancers. Therefore, the aberrant methylation or hypermethylation of these promoters led to the dysregulated expression of cancer-related genes, facilitating the development of malignant tumors. "
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    ABSTRACT: DNA methylation is one of the essential epigenetic mechanisms that are closely correlated with the mechanisms underlying cell growth, differentiation and transformation in eukaryotes. Global changes in the epigenetic landscape are considered to be a hallmark of cancer. The initiation and progression of cancer are mediated through epigenetic modifications along with genetic alterations. Aberrant methylation of promoter regions is an epigenetic abnormality of the human genome that is highly characteristic of cancer. In this review, we aimed to summarize our current understanding of the alterations in the epigenetic landscape and investigate the potential use of DNA and RNA methylation in effective molecular treatment strategies.
    05/2014; 2(3):326-330. DOI:10.3892/br.2014.237
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