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      Therapeutics and Clinical Risk Management (submit here)

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      The association between methylated CDKN2A and cervical carcinogenesis, and its diagnostic value in cervical cancer: a meta-analysis


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          Cervical cancer is the second deadliest gynecologic malignancy, characterized by apparently precancerous lesions and cervical intraepithelial neoplasia (CIN), and having a long course from the development of CIN to cervical cancer. Cyclin-dependent kinase inhibitor 2A ( CDKN2A) is a well-documented tumor suppressor gene and is commonly methylated in cervical cancer. However, the relationship between methylated CDKN2A and carcinogenesis in cervical cancer is inconsistent, and the diagnostic accuracy of methylated CDKN2A is underinvestigated. In this study, we attempted to quantify the association between CDKN2A methylation and the carcinogenesis of cervical cancer, and its diagnostic power.


          We systematically reviewed four electronic databases and identified 26 studies involving 1,490 cervical cancers, 1,291 CINs, and 964 controls. A pooled odds ratio (OR) with corresponding 95% confidence intervals (95% CI) was calculated to evaluate the association between methylated CDKN2A and the carcinogenesis of cervical cancer. Specificity, sensitivity, the area under the receiver operating characteristic curve, and the diagnostic odds ratio were computed to assess the effect of methylated CDKN2A in the diagnosis of cervical cancer.


          Our results indicated an upward trend in the methylation frequency of CDKN2A in the carcinogenesis of cervical cancer (cancer vs control: OR =23.67, 95% CI =15.54–36.06; cancer vs CIN: OR =2.53, 95% CI =1.79–3.5; CIN vs control: OR =9.68, 95% CI =5.82–16.02). The specificity, sensitivity, area under the receiver operating characteristic curve, and diagnostic odds ratio were 0.99 (95% CI: 0.97–0.99), 0.36 (95% CI: 0.28–0.45), 0.93 (95% CI: 0.91–0.95), and 43 (95% CI: 19–98), respectively.


          Our findings indicate that abnormal CDKN2A methylation may be strongly correlated with the pathogenesis of cervical cancer. Our results also demonstrate that CDKN2A methylation might serve as an early detector of cervical cancer. These findings require further confirmation.

          Most cited references64

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          Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine.

          The clinical performance of a laboratory test can be described in terms of diagnostic accuracy, or the ability to correctly classify subjects into clinically relevant subgroups. Diagnostic accuracy refers to the quality of the information provided by the classification device and should be distinguished from the usefulness, or actual practical value, of the information. Receiver-operating characteristic (ROC) plots provide a pure index of accuracy by demonstrating the limits of a test's ability to discriminate between alternative states of health over the complete spectrum of operating conditions. Furthermore, ROC plots occupy a central or unifying position in the process of assessing and using diagnostic tools. Once the plot is generated, a user can readily go on to many other activities such as performing quantitative ROC analysis and comparisons of tests, using likelihood ratio to revise the probability of disease in individual subjects, selecting decision thresholds, using logistic-regression analysis, using discriminant-function analysis, or incorporating the tool into a clinical strategy by using decision analysis.
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            5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy.

            5-Azacytidine was first synthesized almost 40 years ago. It was demonstrated to have a wide range of anti-metabolic activities when tested against cultured cancer cells and to be an effective chemotherapeutic agent for acute myelogenous leukemia. However, because of 5-azacytidine's general toxicity, other nucleoside analogs were favored as therapeutics. The finding that 5-azacytidine was incorporated into DNA and that, when present in DNA, it inhibited DNA methylation, led to widespread use of 5-azacytidine and 5-aza-2'-deoxycytidine (Decitabine) to demonstrate the correlation between loss of methylation in specific gene regions and activation of the associated genes. There is now a revived interest in the use of Decitabine as a therapeutic agent for cancers in which epigenetic silencing of critical regulatory genes has occurred. Here, the current status of our understanding of the mechanism(s) by which 5-azacytosine residues in DNA inhibit DNA methylation is reviewed with an emphasis on the interactions of these residues with bacterial and mammalian DNA (cytosine-C5) methyltransferases. The implications of these mechanistic studies for development of less toxic inhibitors of DNA methylation are discussed.
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              Cancer epigenetics comes of age.

              The discovery of numerous hypermethylated promoters of tumour-suppressor genes, along with a better understanding of gene-silencing mechanisms, has moved DNA methylation from obscurity to recognition as an alternative mechanism of tumour-suppressor inactivation in cancer. Epigenetic events can also facilitate genetic damage, as illustrated by the increased mutagenicity of 5-methylcytosine and the silencing of the MLH1 mismatch repair gene by DNA methylation in colorectal tumours. We review here current mechanistic understanding of the role of DNA methylation in malignant transformation, and suggest Knudson's two-hit hypothesis should now be expanded to include epigenetic mechanisms of gene inactivation.

                Author and article information

                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                18 August 2016
                : 12
                : 1249-1260
                [1 ]Department of Biochemistry and Molecular Biology, School of Medicine, Ningbo University
                [2 ]Department of Medical Oncology, Affiliated Hospital, Ningbo University
                [3 ]Department of Molecular Diagnosis, Ningbo Diagnostic Pathology Center, Ningbo, Zhejiang, People’s Republic of China
                Author notes
                Correspondence: Meng Ye, The Affiliated Hospital, Renming Road, Ningbo, Zhejiang 315000, People’s Republic of China, Tel +86 574 135 6600 2088, Fax +86 574 8703 5866, Email yemeng@ 123456nbu.edu.cn

                These authors are co-first authors of this work

                © 2016 Li et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                p16,methylation,cervical cancer carcinogenesis
                p16, methylation, cervical cancer carcinogenesis


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