title: Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma.
abstract: Early detection of the highly aggressive malignancy cholangiocarcinoma (CCA) remains a challenge but has the potential to render the tumor curable by surgical removal. This study evaluates a biomarker panel for the diagnosis of CCA by DNA methylation analyses of biliary brush samples. The methylation status of 13 candidate genes (CDO1, CNRIP1, DCLK1, FBN1, INA, MAL, SEPT9, SFRP1, SNCA, SPG20, TMEFF2, VIM, and ZSCAN18) was investigated in 93 tissue samples (39 CCAs and 54 nonmalignant controls) using quantitative methylation-specific polymerase chain reaction. The 13 genes were further analyzed in a test series of biliary brush samples (15 CCAs and 20 nonmalignant primary sclerosing cholangitis controls), and the methylation status of the four best performing markers was validated (34 CCAs and 34 primary sclerosing cholangitis controls). Receiver operating characteristic curve analyses were used to evaluate the performance of individual biomarkers and the combination of biomarkers. The 13 candidate genes displayed a methylation frequency of 26%-82% in tissue samples. The four best-performing genes (CDO1, CNRIP1, SEPT9, and VIM) displayed individual methylation frequencies of 45%-77% in biliary brushes from CCA patients. Across the test and validation biliary brush series, this four-gene biomarker panel achieved a sensitivity of 85% and a specificity of 98%, with an area under the receiver operating characteristic curve of 0.944.
  
  
  CONCLUSIONS
  We report a straightforward biomarker assay with high sensitivity and specificity for CCA, outperforming standard brush cytology, and suggest that the biomarker panel, potentially in combination with cytological evaluation, may improve CCA detection, particularly among primary sclerosing cholangitis patients.
authors: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
authors: Kim
authors: K
authors: Andresen
authors: Kirsten Muri
authors: KM
authors: Boberg
authors: Hege Marie
authors: HM
authors: Vedeld
authors: Hilde
authors: H
authors: Honne
authors: Peter
authors: P
authors: Jebsen
authors: Merete
authors: M
authors: Hektoen
authors: Christopher A
authors: CA
authors: Wadsworth
authors: Ole Petter
authors: OP
authors: Clausen
authors: Knut E A
authors: KE
authors: Lundin
authors: Vemund
authors: V
authors: Paulsen
authors: Aksel
authors: A
authors: Foss
authors: Øystein
authors: Ø
authors: Mathisen
authors: Lars
authors: L
authors: Aabakken
authors: Erik
authors: E
authors: Schrumpf
authors: Ragnhild A
authors: RA
authors: Lothe
authors: Guro E
authors: GE
authors: Lind
mesh_terms: D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D005819:Genetic Markers; D006801:Humans; D015203:Reproducibility of Results
chemical_list: D005819:Genetic Markers
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