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. 2016 Aug 18:12:1249-60.
doi: 10.2147/TCRM.S108094. eCollection 2016.

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

Jinyun Li  1 , Chongchang Zhou  2 , Haojie Zhou  3 , Tianlian Bao  2 , Tengjiao Gao  2 , Xiangling Jiang  2 , Meng Ye  1
Affiliations

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

Jinyun Li et al. Ther Clin Risk Manag. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: cervical cancer carcinogenesis; methylation; p16.

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Figures

Figure 1
Figure 1
The flow diagram of the stepwise selection from relevant studies. Abbreviation: CNKI, China National Knowledge Infrastructure.
Figure 2
Figure 2
Forest plot of CDKN2A methylation status during the carcinogenesis of cervical cancer. Note: Weights are from random effects analysis. Abbreviations: CDKN2A, cyclin-dependent kinase inhibitor 2A; CI, confidence interval; CIN, cervical intraepithelial neoplasia; OR, odds ratio.
Figure 2
Figure 2
Forest plot of CDKN2A methylation status during the carcinogenesis of cervical cancer. Note: Weights are from random effects analysis. Abbreviations: CDKN2A, cyclin-dependent kinase inhibitor 2A; CI, confidence interval; CIN, cervical intraepithelial neoplasia; OR, odds ratio.
Figure 3
Figure 3
Funnel plot of publication biases on the relationships between abnormal CDKN2A promoter methylation and the pathogenesis of cervical cancer. Abbreviations: CDKN2A, cyclin-dependent kinase inhibitor 2A; CIN, cervical intraepithelial neoplasia; SE, standard error; OR, odds ratio.
Figure 4
Figure 4
Begg’s funnel plot of publication bias test after trim-and-fill method. Abbreviation: SE, standard error.
Figure 5
Figure 5
Forest sensitivity and specificity of methylated CDKN2A for differentiation of pancreatic mass. Abbreviations: CDKN2A, cyclin-dependent kinase inhibitor 2A; CI, confidence interval; df, degrees of freedom.
Figure 6
Figure 6
SROC plot with best-fitting asymmetric curve of methylated CDKN2A for cervical cancer diagnosis. Abbreviations: AUC, area under the receiver operating characteristic curve; SROC, summary of receiver operating characteristic; SENS, sensitivity; SPEC, specificity.
Figure 7
Figure 7
Fagan plot analysis to evaluate the clinical utility of methylated CDKN2A for identification of cervical cancer. Note: With a pretest probability of cervical cancer of 25% (A), 50% (B), and (C) 75% the post-test probability of cervical cancer. Abbreviations: CDKN2A, cyclin-dependent kinase inhibitor 2A; LR, likelihood ratio.
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