title: Novel target genes and a valid biomarker panel identified for cholangiocarcinoma.
abstract: Cholangiocarcinoma is notoriously difficult to diagnose, and the mortality rate is high due to late clinical presentation. CpG island promoter methylation is frequently seen in cancer development. In the present study, we aimed at identifying novel epigenetic biomarkers with the potential to improve the diagnostic accuracy of cholangiocarcinoma. Microarray data analyses of cholangiocarcinoma cell lines treated with epigenetic drugs and their untreated counterparts were compared with previously published gene expression profiles of primary tumors and with non-malignant controls. Genes responding to the epigenetic treatment that were simultaneously downregulated in primary cholangiocarcinoma compared with controls (n = 43) were investigated for their promoter methylation status in cancer cell lines from the gastrointestinal tract. Genes commonly methylated in cholangiocarcinoma cell lines were subjected to quantitative methylation-specific polymerase chain reaction in a total of 93 clinical samples (cholangiocarcinomas and non-malignant controls). CDO1, DCLK1, SFRP1 and ZSCAN18, displayed high methylation frequencies in primary tumors and were unmethylated in controls. At least one of these four biomarkers was positive in 87% of the tumor samples, with a specificity of 100%. In conclusion, the novel methylation-based biomarker panel showed high sensitivity and specificity for cholangiocarcinoma. The potential of these markers in early diagnosis of this cancer type should be further explored.
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radiumhospital, Oslo, Norway.
authors.forename: Kim
authors.initials: K
authors.lastname: Andresen
authors.forename: Kirsten Muri
authors.initials: KM
authors.lastname: Boberg
authors.forename: Hege Marie
authors.initials: HM
authors.lastname: Vedeld
authors.forename: Hilde
authors.initials: H
authors.lastname: Honne
authors.forename: Merete
authors.initials: M
authors.lastname: Hektoen
authors.forename: Chrisopher A
authors.initials: CA
authors.lastname: Wadsworth
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Clausen
authors.forename: Tom Hemming
authors.initials: TH
authors.lastname: Karlsen
authors.forename: Aksel
authors.initials: A
authors.lastname: Foss
authors.forename: Oystein
authors.initials: O
authors.lastname: Mathisen
authors.forename: Erik
authors.initials: E
authors.lastname: Schrumpf
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
mesh_terms: D001650:Bile Duct Neoplasms / Q000175:diagnosis / Q000235:genetics*; D001653:Bile Ducts, Intrahepatic; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000175:diagnosis / Q000235:genetics*; D018899:CpG Islands; D050558:Cysteine Dioxygenase / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000089742:Doublecortin-Like Kinases; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D014408:Biomarkers, Tumor; D050558:Cysteine Dioxygenase; D004268:DNA-Binding Proteins; D000089742:Doublecortin-Like Kinases; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C579733:ZSCAN18 protein, human; C579734:CDO1 protein, human; C117347:DCLK1 protein, human