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Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma
Author(s) -
Andresen Kim,
Boberg Kirsten Muri,
Vedeld Hege Marie,
Honne Hilde,
Jebsen Peter,
Hektoen Merete,
Wadsworth Christopher A.,
Clausen Ole Petter,
Lundin Knut E.A.,
Paulsen Vemund,
Foss Aksel,
Mathisen Øystein,
Aabakken Lars,
Schrumpf Erik,
Lothe Ragnhild A.,
Lind Guro E.
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27707
Subject(s) - biomarker , primary sclerosing cholangitis , methylation , dna methylation , malignancy , receiver operating characteristic , medicine , biomarker discovery , pathology , biology , gene , genetics , gene expression , disease , proteomics
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. Conclusion : 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. (H epatology 2015;61:1651–1659)