{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:21:08Z","timestamp":1787498468847,"version":"build-2736575974"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T00:00:00Z","timestamp":1620000000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:p>\n                    Cholangiocarcinoma (CCA) has poor prognosis due to late\u2010stage, symptomatic presentation. Altered DNA methylation markers may improve diagnosis of CCA. Reduced\u2010representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin\u2010fixed, paraffin\u2010embedded CCA tumors and adjacent hepatobiliary control tissues using methylation\u2010specific polymerase chain reaction. Selected MDMs were then blindly assayed on DNA extracted from independent archival biliary brushing specimens, including 12 perihilar cholangiocarcinoma, 4 distal cholangiocarcinoma cases, and 18 controls. Next, MDMs were blindly assayed on plasma DNA from patients with extrahepatic CCA (eCCA), including 54 perihilar CCA and 5 distal CCA cases and 95 healthy and 22 primary sclerosing cholangitis controls, balanced for age and sex. From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. In the clinical pilot of 16 MDMs on cytology brushings, methylated\n                    <jats:italic toggle=\"yes\">EMX1<\/jats:italic>\n                    (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.95\u20101.0). In the clinical pilot on plasma, a cross\u2010validated recursive partitioning tree prediction model from nine MDMs was accurate for\n                    <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                    eCCA (AUC, 0.88 [0.81\u20100.95]) but not for primary sclerosing cholangitis\u2013associated eCCA (AUC, 0.54 [0.35\u20100.73]).\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : Next\u2010generation DNA sequencing yielded highly discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA.\n                  <\/jats:p>","DOI":"10.1002\/hep4.1730","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T11:51:48Z","timestamp":1620042708000},"page":"1448-1459","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":34,"title":["DNA Methylation Markers for Detection of Cholangiocarcinoma: Discovery, Validation, and Clinical Testing in Biliary Brushings and Plasma"],"prefix":"10.1097","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7834-9825","authenticated-orcid":false,"given":"Ju Dong","family":"Yang","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Cedars\u2010Sinai Medical Center,Los 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Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Cao","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick H.","family":"Foote","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasra H.","family":"Giama","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily G.","family":"Barr Fritcher","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology,Mayo Clinic,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas 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