Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets

Background: Promoter hypermethylation in death-associated protein kinase 1 (DAPK1) gene has been long linked to cervical neoplasia, but the established results remained controversial. Here, we performed a meta-analysis to assess the associations of DAPK1 promoter hypermethylation with low-grade intr...

Descripción completa

Detalles Bibliográficos
Autores principales: Wang, Xue-bin, Cui, Ning-hua, Liu, Xia-nan, Ma, Jun-fen, Zhu, Qing-hua, Guo, Shu-ren, Zhao, Jun-wei, Ming, Liang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056635/
https://www.ncbi.nlm.nih.gov/pubmed/30065752
http://dx.doi.org/10.3389/fgene.2018.00258
_version_ 1783341373301194752
author Wang, Xue-bin
Cui, Ning-hua
Liu, Xia-nan
Ma, Jun-fen
Zhu, Qing-hua
Guo, Shu-ren
Zhao, Jun-wei
Ming, Liang
author_facet Wang, Xue-bin
Cui, Ning-hua
Liu, Xia-nan
Ma, Jun-fen
Zhu, Qing-hua
Guo, Shu-ren
Zhao, Jun-wei
Ming, Liang
author_sort Wang, Xue-bin
collection PubMed
description Background: Promoter hypermethylation in death-associated protein kinase 1 (DAPK1) gene has been long linked to cervical neoplasia, but the established results remained controversial. Here, we performed a meta-analysis to assess the associations of DAPK1 promoter hypermethylation with low-grade intra-epithelial lesion (HSIL), high-grade intra-epithelial lesion (HSIL), cervical cancer (CC), and clinicopathological features of CC. Methods: Published studies with qualitative methylation data were initially searched from PubMed, Web of Science, EMBASE, and China National Knowledge Infrastructure databases (up to March 2018). Then, quantitative methylation datasets, retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, were pooled to validate the results of published studies. Results: In a meta-analysis of 37 published studies, DAPK1 promoter hypermethylation progressively increased the risk of LSIL by 2.41-fold (P = 0.012), HSIL by 7.62-fold (P < 0.001), and CC by 23.17-fold (P < 0.001). Summary receiver operating characteristic curves suggested a potential diagnostic value of DAPK1 promoter hypermethylation in CC, with a large area-under-the-curve of 0.83, a high specificity of 97%, and a moderate sensitivity of 59%. There were significant impacts of DAPK1 promoter hypermethylation on histological type (odds ratio (OR) = 3.53, P < 0.001) and FIGO stage of CC (OR = 2.15, P = 0.003). Then, a pooled analysis of nine TCGA and GEO datasets, covering 13 CPG sites within DAPK1 promoter, identified eight CC-associated sites, six sites with diagnostic values for CC (pooled specificities: 74–90%; pooled sensitivities: 70–81%), nine loci associated with the histological type of CC, and all 13 loci with down-regulated effects on DAPK1 mRNA expression. Conclusion: The meta-analysis suggests that DAPK1 promoter hypermethylation is significantly associated with the disease severity of cervical neoplasia. DAPK1 methylation detection exhibits a promising ability to discriminate CC from cancer-free controls.
format Online
Article
Text
id pubmed-6056635
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-60566352018-07-31 Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets Wang, Xue-bin Cui, Ning-hua Liu, Xia-nan Ma, Jun-fen Zhu, Qing-hua Guo, Shu-ren Zhao, Jun-wei Ming, Liang Front Genet Genetics Background: Promoter hypermethylation in death-associated protein kinase 1 (DAPK1) gene has been long linked to cervical neoplasia, but the established results remained controversial. Here, we performed a meta-analysis to assess the associations of DAPK1 promoter hypermethylation with low-grade intra-epithelial lesion (HSIL), high-grade intra-epithelial lesion (HSIL), cervical cancer (CC), and clinicopathological features of CC. Methods: Published studies with qualitative methylation data were initially searched from PubMed, Web of Science, EMBASE, and China National Knowledge Infrastructure databases (up to March 2018). Then, quantitative methylation datasets, retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, were pooled to validate the results of published studies. Results: In a meta-analysis of 37 published studies, DAPK1 promoter hypermethylation progressively increased the risk of LSIL by 2.41-fold (P = 0.012), HSIL by 7.62-fold (P < 0.001), and CC by 23.17-fold (P < 0.001). Summary receiver operating characteristic curves suggested a potential diagnostic value of DAPK1 promoter hypermethylation in CC, with a large area-under-the-curve of 0.83, a high specificity of 97%, and a moderate sensitivity of 59%. There were significant impacts of DAPK1 promoter hypermethylation on histological type (odds ratio (OR) = 3.53, P < 0.001) and FIGO stage of CC (OR = 2.15, P = 0.003). Then, a pooled analysis of nine TCGA and GEO datasets, covering 13 CPG sites within DAPK1 promoter, identified eight CC-associated sites, six sites with diagnostic values for CC (pooled specificities: 74–90%; pooled sensitivities: 70–81%), nine loci associated with the histological type of CC, and all 13 loci with down-regulated effects on DAPK1 mRNA expression. Conclusion: The meta-analysis suggests that DAPK1 promoter hypermethylation is significantly associated with the disease severity of cervical neoplasia. DAPK1 methylation detection exhibits a promising ability to discriminate CC from cancer-free controls. Frontiers Media S.A. 2018-07-17 /pmc/articles/PMC6056635/ /pubmed/30065752 http://dx.doi.org/10.3389/fgene.2018.00258 Text en Copyright © 2018 Wang, Cui, Liu, Ma, Zhu, Guo, Zhao and Ming. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Wang, Xue-bin
Cui, Ning-hua
Liu, Xia-nan
Ma, Jun-fen
Zhu, Qing-hua
Guo, Shu-ren
Zhao, Jun-wei
Ming, Liang
Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets
title Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets
title_full Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets
title_fullStr Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets
title_full_unstemmed Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets
title_short Identification of DAPK1 Promoter Hypermethylation as a Biomarker for Intra-Epithelial Lesion and Cervical Cancer: A Meta-Analysis of Published Studies, TCGA, and GEO Datasets
title_sort identification of dapk1 promoter hypermethylation as a biomarker for intra-epithelial lesion and cervical cancer: a meta-analysis of published studies, tcga, and geo datasets
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056635/
https://www.ncbi.nlm.nih.gov/pubmed/30065752
http://dx.doi.org/10.3389/fgene.2018.00258
work_keys_str_mv AT wangxuebin identificationofdapk1promoterhypermethylationasabiomarkerforintraepitheliallesionandcervicalcancerametaanalysisofpublishedstudiestcgaandgeodatasets
AT cuininghua identificationofdapk1promoterhypermethylationasabiomarkerforintraepitheliallesionandcervicalcancerametaanalysisofpublishedstudiestcgaandgeodatasets
AT liuxianan identificationofdapk1promoterhypermethylationasabiomarkerforintraepitheliallesionandcervicalcancerametaanalysisofpublishedstudiestcgaandgeodatasets
AT majunfen identificationofdapk1promoterhypermethylationasabiomarkerforintraepitheliallesionandcervicalcancerametaanalysisofpublishedstudiestcgaandgeodatasets
AT zhuqinghua identificationofdapk1promoterhypermethylationasabiomarkerforintraepitheliallesionandcervicalcancerametaanalysisofpublishedstudiestcgaandgeodatasets
AT guoshuren identificationofdapk1promoterhypermethylationasabiomarkerforintraepitheliallesionandcervicalcancerametaanalysisofpublishedstudiestcgaandgeodatasets
AT zhaojunwei identificationofdapk1promoterhypermethylationasabiomarkerforintraepitheliallesionandcervicalcancerametaanalysisofpublishedstudiestcgaandgeodatasets
AT mingliang identificationofdapk1promoterhypermethylationasabiomarkerforintraepitheliallesionandcervicalcancerametaanalysisofpublishedstudiestcgaandgeodatasets