Serum microRNAs as novel biomarkers for primary sclerosing cholangitis and cholangiocarcinoma

Abstract

SummaryThe diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease-associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples [40 PSC, 40 CC,20 primary biliary cirrhosis (PBC) and 40 controls]. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0Á70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR-200c was found to be expressed differentially in PSC versus controls, whereas miR-483-5p and miR-194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR-222 and miR-483-5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC.

Circulating Biomarkers for Cholangiocarcinoma

“…Furthermore, miR-150 revealed an AUC of 0.764 with a sensitivity of 80.6% and specificity of 58.1% for the diagnosis of intrahepatic CCA [29]. In a small study including 30 CCA patients, Bernuzzi et al [30] showed that serum levels of miR-483-p and miR-222 were able to discriminate between PSC and CCA patients. Although most diagnostically evaluated circulating miRNAs are elevated in CCA, some individual miRNAs such as miR-150–5p were shown to be downregulated in serum samples of CCA patients [31].…”

Deregulated MicroRNAs in Biliary Tract Cancer: Functional Targets and Potential Biomarkers

“…Of note, the calculated diagnostic power of certain miRNAs exceeds the diagnostic power of the standard BTC marker, CA19-9, as illustrated in Figure 1(b). However, following the results of the presented studies, it may be useful to not just concentrate on one biomarker but rather combine a certain number of candidate biomarkers in a group to achieve maximum sensitivity, specificity, and diagnostic accuracy [26, 93, 95]. Again, for the mentioned miRNA-21, its aberrant expression in plasma, serum, urine, and tissue has superior diagnostic power in differentiating BTC from BBD and healthy controls, thus qualifying this miRNA as a potential biomarker (Table 2).…”

“…Of note, serum levels of miRNA-26a declined significantly in patients who underwent potential curative surgery [94]. In a large screen for differentially expressed miRNAs in serum of patients with BTC or PSC versus healthy individuals, Bernuzzi et al identified miRNA-200c as being deregulated in PSC with an AUC value of 0.74 for distinguishing PSC from healthy control [95]. For BTC, they found serum levels of miR-483-5p and miR-194 to be enhanced compared to both PSC and controls (with control samples displaying the lowest expression levels).…”

“…ROC curve analysis for both of these miRNA species resulted in AUC of 0.77 for miRNA-483-5p and AUC of 0.74 for miRNA-194. However, combination of these two miRNAs significantly increased the AUC value to 0.81 [95]. MicroRNA-192, which was already found to be upregulated in urine samples of CC patients as mentioned above [98], is another circulating miRNA of potential diagnostic value as published by Silakit and others [96].…”

The role of microRNAs in intrahepatic cholangiocarcinoma

“…Bernuzzi et al 57. performed miRNA expression profiling in 90 serum samples [30 primary sclerosing cholangitis (PSC), 30 cholangiocarcinoma and 30 control cases] to found disease‐associated miRNAs (discovery phase).…”