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Background and Aims  Primary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC.    Approach and Results  Droplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC‐associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77–0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA ≤ 12 months following bile collection increased the accuracy for cancer detection, with a combined sensitivity of 100% (28/28) and a specificity of 90% (20/203). The specificity increased to 93% when only including patients with PSC with longtime follow‐up (> 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls ( n  = 23). Importantly, the bile samples from the CCA‐PSC ≤ 12 patients, all positive for the biomarkers, included both early‐stage and late‐stage CCA, different tumor growth patterns, anatomical locations, and carbohydrate antigen 19‐9 levels.    Conclusions  Using highly sensitive ddPCR to analyze robust epigenetic biomarkers, CCA in PSC was accurately detected in bile, irrespective of clinical and molecular features, up to 12 months before CCA diagnosis. The findings suggest a potential for these biomarkers to complement current detection and screening methods for CCA in patients with PSC.

Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile