Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma - PubMed (original) (raw)

doi: 10.1002/hep.27707. Epub 2015 Feb 24.

Kirsten Muri Boberg, Hege Marie Vedeld, Hilde Honne, Peter Jebsen, Merete Hektoen, Christopher A Wadsworth, Ole Petter Clausen, Knut E A Lundin, Vemund Paulsen, Aksel Foss, Øystein Mathisen, Lars Aabakken, Erik Schrumpf, Ragnhild A Lothe, Guro E Lind

Affiliations

Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma

Kim Andresen et al. Hepatology. 2015 May.

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.

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.

© 2015 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

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Figures

Figure 1

Figure 1

Receiver operating characteristic curves for the four‐gene biomarker panel in all biliary brush samples. The area under the ROC curve is depicted for (A) the biomarkers CDO1, CNRIP1, SEPT9, and VIM and for (B) the combined biomarker panel, which is based on the sum of the four PMR values.

Figure 2

Figure 2

Comparing the performance of the biomarker panel with that of conventional cytology in biliary brush samples. For the biomarker panel (CDO1, CNRIP1, SEPT9, and VIM), see the following color code: red, methylated; green, unmethylated; gray, not available. For cytology: closed circle, positive; open circle, negative (scored according to Boberg et al.4). Control sample 50 has been discussed in the main text. Abbreviations: N/A, not available; N/C, not enough cells present for analysis; N/D, no data.

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