title: Recurrent patterns of DNA methylation in the ZNF154, CASP8, and VHL promoters across a wide spectrum of human solid epithelial tumors and cancer cell lines.
abstract: The study of aberrant DNA methylation in cancer holds the key to the discovery of novel biological markers for diagnostics and can help to delineate important mechanisms of disease. We have identified 12 loci that are differentially methylated in serous ovarian cancers and endometrioid ovarian and endometrial cancers with respect to normal control samples. The strongest signal showed hypermethylation in tumors at a CpG island within the ZNF154 promoter. We show that hypermethylation of this locus is recurrent across solid human epithelial tumor samples for 15 of 16 distinct cancer types from TCGA. Furthermore, ZNF154 hypermethylation is strikingly present across a diverse panel of ENCODE cell lines, but only in those derived from tumor cells. By extending our analysis from the Illumina 27K Infinium platform to the 450K platform, to sequencing of PCR amplicons from bisulfite treated DNA, we demonstrate that hypermethylation extends across the breadth of the ZNF154 CpG island. We have also identified recurrent hypomethylation in two genomic regions associated with CASP8 and VHL. These three genes exhibit significant negative correlation between methylation and gene expression across many cancer types, as well as patterns of DNaseI hypersensitivity and histone marks that reflect different chromatin accessibility in cancer vs. normal cell lines. Our findings emphasize hypermethylation of ZNF154 as a biological marker of relevance for tumor identification. Epigenetic modifications affecting the promoters of ZNF154, CASP8, and VHL are shared across a vast array of tumor types and may therefore be important for understanding the genomic landscape of cancer.
authors.affiliation: Genome Technology Branch; National Human Genome Research Institute; National Institutes of Health; Bethesda, MD USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Vega
authors.affiliation: Genome Technology Branch; National Human Genome Research Institute; National Institutes of Health; Bethesda, MD USA.
authors.forename: Valer
authors.initials: V
authors.lastname: Gotea
authors.affiliation: Genome Technology Branch; National Human Genome Research Institute; National Institutes of Health; Bethesda, MD USA.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Petrykowska
authors.affiliation: Genome Technology Branch; National Human Genome Research Institute; National Institutes of Health; Bethesda, MD USA.
authors.forename: Gennady
authors.initials: G
authors.lastname: Margolin
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences; University of Pittsburgh Medical School; Pittsburgh, PA USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Krivak
authors.affiliation: School of Public Health and Health Services; The George Washington University; Washington DC, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: DeLoia
authors.affiliation: Cancer Genetics Branch; National Human Genome Research Institute; National Institutes of Health; Bethesda, MD USA.
authors.forename: Daphne W
authors.initials: DW
authors.lastname: Bell
authors.affiliation: Genome Technology Branch; National Human Genome Research Institute; National Institutes of Health; Bethesda, MD USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Elnitski
mesh_terms: D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: D002843:Chromatin; D051741:Kruppel-Like Transcription Factors; C000588442:ZNF154 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C505530:CASP8 protein, human; D053181:Caspase 8; C497446:VHL protein, human
keywords: CASP8; DNA methylation; VHL; ZNF154; cancer; chromatin; endometrioid endometrial cancer; endometrioid ovarian cancer; epigenetics; ovarian papillary serous tumors of low malignant potential; pan-cancer; serous ovarian cancer