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Título:
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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
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Autor/a:
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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
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Notas:
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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.
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. |
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Materia(s):
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-Vèrtebres cervicals
-Marcadors tumorals
-Càncer
-Cervical vertebrae
-Tumor markers
-Cancer |
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Derechos:
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(c) Taylor & Francis, 2014
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Tipo de documento:
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Artículo
Artículo - Versión aceptada |
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Editor:
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Taylor & Francis
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Compartir:
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