TY - JOUR
T1 - 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
AU - Brebi, Priscilla
AU - Maldonado, Leonel
AU - Noordhuis, Maartje G.
AU - Ili, Carmen
AU - Leal, Pamela
AU - Garcia, Patricia
AU - Brait, Mariana
AU - Ribas, Judit
AU - Michailidi, Christina
AU - Perez, Jimena
AU - Soudry, Ethan
AU - Tapia, Oscar
AU - Guzman, Pablo
AU - Muñoz, Sergio
AU - Van Neste, Leander
AU - Van Criekinge, Wim
AU - Irizarry, Rafael
AU - Sidransky, David
AU - Roa, Juan C.
AU - Guerrero-Preston, Rafael
N1 - Funding Information:
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 studie-fonds. 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.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Biomarkers
KW - Cervical cancer
KW - Companion diagnostics
KW - MeDIP
KW - Promoter methylation
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U2 - 10.4161/epi.27120
DO - 10.4161/epi.27120
M3 - Article
C2 - 24241165
AN - SCOPUS:84892600329
SN - 1559-2294
VL - 9
SP - 308
EP - 317
JO - Epigenetics
JF - Epigenetics
IS - 2
ER -