title: Robust Detection of DNA Hypermethylation of ZNF154 as a Pan-Cancer Locus with in Silico Modeling for Blood-Based Diagnostic Development.
abstract: Sites that display recurrent, aberrant DNA methylation in cancer represent potential biomarkers for screening and diagnostics. Previously, we identified hypermethylation at the ZNF154 CpG island in 15 solid epithelial tumor types from 13 different organs. In this study, we measure the magnitude and pattern of differential methylation of this region across colon, lung, breast, stomach, and endometrial tumor samples using next-generation bisulfite amplicon sequencing. We found that all tumor types and subtypes are hypermethylated at this locus compared with normal tissue. To evaluate this site as a possible pan-cancer marker, we compare the ability of several sequence analysis methods to distinguish the five tumor types (184 tumor samples) from normal tissue samples (n = 34). The classification performance for the strongest method, measured by the area under (the receiver operating characteristic) curve (AUC), is 0.96, close to a perfect value of 1. Furthermore, in a computational simulation of circulating tumor DNA, we were able to detect limited amounts of tumor DNA diluted with normal DNA: 1% tumor DNA in 99% normal DNA yields AUCs of up to 0.79. Our findings suggest that hypermethylation of the ZNF154 CpG island is a relevant biomarker for identifying solid tumor DNA and may have utility as a generalizable biomarker for circulating tumor DNA.
authors: Translational and Functional Genomics Branch, National Human Genome Research Institute, Rockville, Maryland.
authors: Gennady
authors: G
authors: Margolin
authors: Translational and Functional Genomics Branch, National Human Genome Research Institute, Rockville, Maryland.
authors: Hanna M
authors: HM
authors: Petrykowska
authors: Translational and Functional Genomics Branch, National Human Genome Research Institute, Rockville, Maryland.
authors: Nader
authors: N
authors: Jameel
authors: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland.
authors: Daphne W
authors: DW
authors: Bell
authors: National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute, Rockville, Maryland.
authors: Alice C
authors: AC
authors: Young
authors: Translational and Functional Genomics Branch, National Human Genome Research Institute, Rockville, Maryland. Electronic address: elnitski@mail.nih.gov.
authors: Laura
authors: L
authors: Elnitski
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D003198:Computer Simulation; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood*; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000097:blood* / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D021141:Nucleic Acid Amplification Techniques / Q000379:methods; D012372:ROC Curve; D015203:Reproducibility of Results; D013447:Sulfites / Q000737:chemistry
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D051741:Kruppel-Like Transcription Factors; D013447:Sulfites; C000588442:ZNF154 protein, human; C042345:hydrogen sulfite