Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population

Cervical cancer is a major health concern among women in Latin America due to its high incidence and mortality. Therefore, the discovery of molecular markers for cervical cancer screening and triage is imperative. The aim of this study was to use a genome wide DNA methylation approach to identify no...

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Autores: Brebi, Priscilla, Maldonado, Leonel, Noordhuis, Maartje G., Ili, Carmen, Leal, Pamela, Garcia, Patricia, Brait, Mariana, Ribas i Fortuny, Judit, Michailidi, Christina, Perez, Jimena, Soudry, Ethan, Tapia, Oscar, Guzman, Pablo, Muñoz, Sergio, Van Neste, Leander, Van Criekinge, Wim, Irizarry, Rafael, Sidransky, David, Roa, Juan C., Guerrero-Preston, Rafael
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2014
País:España
Institución:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/60286
Acceso en línea:https://doi.org/10.4161/epi.27120
http://hdl.handle.net/10459.1/60286
Access Level:acceso abierto
Palabra clave:Vèrtebres cervicals
Marcadors tumorals
Càncer
Cervical vertebrae
Tumor markers
Cancer
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spelling Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean populationBrebi, PriscillaMaldonado, LeonelNoordhuis, Maartje G.Ili, CarmenLeal, PamelaGarcia, PatriciaBrait, MarianaRibas i Fortuny, JuditMichailidi, ChristinaPerez, JimenaSoudry, EthanTapia, OscarGuzman, PabloMuñoz, SergioVan Neste, LeanderVan Criekinge, WimIrizarry, RafaelSidransky, DavidRoa, Juan C.Guerrero-Preston, RafaelVèrtebres cervicalsMarcadors tumoralsCàncerCervical vertebraeTumor markersCancerCervical cancer is a major health concern among women in Latin America due to its high incidence and mortality. Therefore, the discovery of molecular markers for cervical cancer screening and triage is imperative. The aim of this study was to use a genome wide DNA methylation approach to identify novel methylation biomarkers in cervical cancer. DNA from normal cervical mucosa and cervical cancer tissue samples from Chile was enriched with Methylated DNA Immunoprecipitation (MeDIP), hybridized to oligonucleotide methylation microarrays and analyzed with a stringent bioinformatics pipeline to identify differentially methylated regions (DMRs) as candidate biomarkers. Quantitative Methylation Specific PCR (qMSP) was used to study promoter methylation of candidate DMRs in clinical samples from two independent cohorts. HPV detection and genotyping were performed by Reverse Line Blot analysis. Bioinformatics analysis revealed GGTLA4, FKBP6, ZNF516, SAP130, and INTS1 to be differentially methylated in cancer and normal tissues in the Discovery cohort. In the Validation cohort FKBP6 promoter methylation had 73% sensitivity and 80% specificity (AUC = 0.80). ZNF516 promoter methylation was the best biomarker, with both sensitivity and specificity of 90% (AUC = 0.92), results subsequently corroborated in a Prevalence cohort. Together, ZNF516 and FKBP6 exhibited a sensitivity of 84% and specificity of 81%, when considering both cohorts. Our genome wide DNA methylation assessment approach (MeDIP-chip) successfully identified novel biomarkers that differentiate between cervical cancer and normal samples, after adjusting for age and HPV status. These biomarkers need to be further explored in case-control and prospective cohorts to validate them as cervical cancer biomarkers.This research was supported in part by National Cancer Institute grants K01-CA164092 and U01-CA84986; and CONICYT, Proyecto de Atracción de Capital Humano - Modalidad de Estadía Corta de la Comisión Nacional de Ciencia y Tecnología, Chile (Guerrero-Preston R.); CORFO, Centro de Excelencia en Estudios Genéticos e Inmunológicos (CEGIN) 09CN14–5960, Scientific and Technological Bioresource Nucleus (BIOREN); Brebi P is recipient of grants from the FONDECYT Proyecto Postdoctorado 3120141. Noordhuis MG is recipient of grants from the Dutch Cancer Society and Jo Kolk studiefonds. Ili C is recipient of grants from FONDECYT Proyecto Postdoctorado 3130630. Soudry E is recipient of a fellowship grant from the American Physicians Fellowship for Medicine in Israel.Taylor & Francis2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://doi.org/10.4161/epi.27120http://hdl.handle.net/10459.1/60286reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésVersió postprint del document publicat a: https://doi.org/10.4161/epi.27120Epigenetics, 2014, vol. 9, num. 2, p. 308-317(c) Taylor & Francis, 2014info:eu-repo/semantics/openAccessoai:repositori.udl.cat:10459.1/602862026-06-24T12:42:17Z
dc.title.none.fl_str_mv Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population
title Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population
spellingShingle Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population
Brebi, Priscilla
Vèrtebres cervicals
Marcadors tumorals
Càncer
Cervical vertebrae
Tumor markers
Cancer
title_short Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population
title_full Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population
title_fullStr Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population
title_full_unstemmed Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population
title_sort Genome-wide methylation profiling reveals Zinc finger protein 516 (ZNF516) and FK-506-binding protein 6 (FKBP6) promoters frequently methylated in cervical neoplasia, associated with HPV status and ethnicity in a Chilean population
dc.creator.none.fl_str_mv Brebi, Priscilla
Maldonado, Leonel
Noordhuis, Maartje G.
Ili, Carmen
Leal, Pamela
Garcia, Patricia
Brait, Mariana
Ribas i Fortuny, Judit
Michailidi, Christina
Perez, Jimena
Soudry, Ethan
Tapia, Oscar
Guzman, Pablo
Muñoz, Sergio
Van Neste, Leander
Van Criekinge, Wim
Irizarry, Rafael
Sidransky, David
Roa, Juan C.
Guerrero-Preston, Rafael
author Brebi, Priscilla
author_facet Brebi, Priscilla
Maldonado, Leonel
Noordhuis, Maartje G.
Ili, Carmen
Leal, Pamela
Garcia, Patricia
Brait, Mariana
Ribas i Fortuny, Judit
Michailidi, Christina
Perez, Jimena
Soudry, Ethan
Tapia, Oscar
Guzman, Pablo
Muñoz, Sergio
Van Neste, Leander
Van Criekinge, Wim
Irizarry, Rafael
Sidransky, David
Roa, Juan C.
Guerrero-Preston, Rafael
author_role author
author2 Maldonado, Leonel
Noordhuis, Maartje G.
Ili, Carmen
Leal, Pamela
Garcia, Patricia
Brait, Mariana
Ribas i Fortuny, Judit
Michailidi, Christina
Perez, Jimena
Soudry, Ethan
Tapia, Oscar
Guzman, Pablo
Muñoz, Sergio
Van Neste, Leander
Van Criekinge, Wim
Irizarry, Rafael
Sidransky, David
Roa, Juan C.
Guerrero-Preston, Rafael
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Vèrtebres cervicals
Marcadors tumorals
Càncer
Cervical vertebrae
Tumor markers
Cancer
topic Vèrtebres cervicals
Marcadors tumorals
Càncer
Cervical vertebrae
Tumor markers
Cancer
description Cervical cancer is a major health concern among women in Latin America due to its high incidence and mortality. Therefore, the discovery of molecular markers for cervical cancer screening and triage is imperative. The aim of this study was to use a genome wide DNA methylation approach to identify novel methylation biomarkers in cervical cancer. DNA from normal cervical mucosa and cervical cancer tissue samples from Chile was enriched with Methylated DNA Immunoprecipitation (MeDIP), hybridized to oligonucleotide methylation microarrays and analyzed with a stringent bioinformatics pipeline to identify differentially methylated regions (DMRs) as candidate biomarkers. Quantitative Methylation Specific PCR (qMSP) was used to study promoter methylation of candidate DMRs in clinical samples from two independent cohorts. HPV detection and genotyping were performed by Reverse Line Blot analysis. Bioinformatics analysis revealed GGTLA4, FKBP6, ZNF516, SAP130, and INTS1 to be differentially methylated in cancer and normal tissues in the Discovery cohort. In the Validation cohort FKBP6 promoter methylation had 73% sensitivity and 80% specificity (AUC = 0.80). ZNF516 promoter methylation was the best biomarker, with both sensitivity and specificity of 90% (AUC = 0.92), results subsequently corroborated in a Prevalence cohort. Together, ZNF516 and FKBP6 exhibited a sensitivity of 84% and specificity of 81%, when considering both cohorts. Our genome wide DNA methylation assessment approach (MeDIP-chip) successfully identified novel biomarkers that differentiate between cervical cancer and normal samples, after adjusting for age and HPV status. These biomarkers need to be further explored in case-control and prospective cohorts to validate them as cervical cancer biomarkers.
publishDate 2014
dc.date.none.fl_str_mv 2014
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.4161/epi.27120
http://hdl.handle.net/10459.1/60286
url https://doi.org/10.4161/epi.27120
http://hdl.handle.net/10459.1/60286
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.4161/epi.27120
Epigenetics, 2014, vol. 9, num. 2, p. 308-317
dc.rights.none.fl_str_mv (c) Taylor & Francis, 2014
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Taylor & Francis, 2014
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Taylor & Francis
publisher.none.fl_str_mv Taylor & Francis
dc.source.none.fl_str_mv reponame:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
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