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Background/Aim: Cholangiocarcinoma (CCA) is a type of liver cancer originating from bile duct epithelium which has an unfavorable prognosis. Therefore, novel prognostic markers and effective therapeutic regimens are required. Opioid-binding protein/cell adhesion molecule-like (OPCML) is a tumor-suppressor protein that suppresses CCA cell proliferation via AXL receptor tyrosine kinase/signal transducer and activator of transcription 3 (AXL/STAT3) inactivation. However, this association in clinical samples remains unknown. We aimed to determine OPCML and AXL expression and investigate their association with clinicopathological features in patients with CCA. In addition, we also addressed whether OPCML enhanced the sensitivity of CCA cells to AXL inhibitor R428 in vitro. Materials and Methods: The expression of OPCML and AXL was determined by immunohistochemistry in 90 CCA tissue samples. The study of CCA cell line sensitivity to R428 was performed by cell viability assay. Results: The expression of OPCML was significantly lower while AXL expression was substantially higher in CCA than in adjacent normal tissue (p

DNA methylation can regulate the expression of tumour suppressor genes P16 and TP53, environmental factors, which are both important factors related to an increased risk and prognosis of oesophageal cancer (EC). However, the association between these two genes methylation status, as well as the effects of gene-environment interactions, EC risk remains unclear. A Hospital-based case-control study data were collected from 105 new EC cases and 108 controls. Promoter methylation status was investigated for P16 and TP53 genes using methylation-specific polymerase (MSP) chain reaction methods with SYBR green. Logistic and Cox regression models were used to analyse the association of P16 and TP53 promotor methylation status with EC risk and prognosis, respectively. Our results suggest P16, TP53 methylation significantly increased the risk of EC (OR = 5.24, 95% CI: 2.57-10.66, P 0.001; OR = 3.38, 95% CI: 1.17-6.67, P 0.001, respectively). In addition, P16 and TP53 promoter methylation status and the combined effects between environmental factors and its methylations in tissue were correlated with the EC risk and prognosis of EC patients. As a new biomarker, the methylation of P16 and TP53 can serve as a potential predictive biomarker of EC.

Summary Biliary tract cancers (BTCs) currently have no approved targeted therapies. Although genomic profiling of primary BTCs has identified multiple potential drug targets, accurate models are needed for their evaluation. Genomic profiling of 22 BTC cell lines revealed they harbor similar mutational signatures, recurrently mutated genes, and genomic alterations to primary tumors. Transcriptomic profiling identified two major subtypes, enriched for epithelial and mesenchymal genes, which were also evident in patient-derived organoids and primary tumors. Interrogating these models revealed multiple mechanisms of MAPK signaling activation in BTC, including co-occurrence of low-activity BRAF and MEK mutations with receptor tyrosine kinase overexpression. Finally, BTC cell lines with altered ERBB2 or FGFRs were exquisitely sensitive to specific targeted agents, whereas surprisingly, IDH1-mutant lines did not respond to IDH1 inhibitors in vitro. These findings establish BTC cell lines as robust models of primary disease, reveal specific molecular disease subsets, and highlight specific molecular vulnerabilities in these cancers., Graphical Abstract, Highlights • BTC cell lines harbor similar genomic alterations to primary tumors • Transcriptomic profiling of BTC cell lines identified two molecular subtypes • MAPK signaling is activated in BTC via multiple mechanisms • BTC lines with deregulated ERBB2 or FGFRs respond to specific targeted therapies, Biological Sciences; Genetics; Genomics; Cancer

Cholangiocarcinoma (CCA) is a fatal liver cancer arising from bile duct epithelium. Polycomb repressive complex 2 (PRC2) is a histone methyltransferase enzyme that catalyzes trimethylation of histone H3 on lysine 27, resulting transcriptional gene silencing. The key components of PRC2 are EZH2, SUZ12 and EED, which EZH2 is a catalytic subunit. The defect of individual PRC2 components has been shown to enhance carcinogenesis and cancer progression. The aim of this study was to determine the expression of individual PRC2 components and evaluate its association with clinicopathological data in CCA patients.The expression of PRC2 components including EZH2, SUZ12 and EED was determined by immunohistochemistry in 40 CCA tissue samples.The expression of EZH2 and SUZ12 in CCA tissue was significantly higher than that in adjacent non-cancerous tissue (P 0.001). The high cytoplasmic EZH2 expression was significantly associated with short overall survival in CCA (P = 0.030). Interestingly, a combined high nuclear and cytoplasmic expression of EZH2 was found to be a worse prognostic marker for overall survival (P = 0.015). Moreover, combined high expression of EZH2 and SUZ12/EED was also associated with short overall survival (P 0.05).Our findings suggest that overexpression of the PRC2 key components especially EZH2 in both nucleus and cytoplasm can be potentially used as a prognostic marker for CCA.

Background Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct epithelial cell lining. The misdiagnosis of CCA and other biliary diseases may occur due to the similarity of clinical manifestations and blood tests resulting in inappropriate or delayed treatment. Thus, an accurate and less-invasive method for differentiating CCA from other biliary diseases is inevitable. Methods We quantified methylation of OPCML, HOXA9, and HOXD9 in serum cell-free DNA (cfDNA) of CCA patients and other biliary diseases using methylation-sensitive high-resolution melting (MS-HRM). Their potency as differential biomarkers between CCA and other biliary diseases was also evaluated by using receiver operating characteristic (ROC) curves. Results The significant difference of methylation levels of OPCML and HOXD9 was observed in serum cfDNA of CCA compared to other biliary diseases. Assessment of serum cfDNA methylation of OPCML and HOXD9 as differential biomarkers of CCA and other biliary diseases showed the area under curve (AUC) of 0.850 (0.759–0.941) for OPCML which sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 80.00%, 90.00%, 88.88%, 81.81%, and 85.00%, respectively. The AUC of HOXD9 was 0.789 (0.686–0.892) with sensitivity, specificity, PPV, NPV, and accuracy of 67.50%, 90.00%, 87.09%, 73.46%, and 78.75%, respectively. The combined marker between OPCML and HOXD9 showed sensitivity, specificity, PPV, and NPV of 62.50%, 100%, 100%, and 72.72%, respectively, which may be helpful to prevent a misdiagnosis between CCA and other biliary diseases. Conclusions Our findings suggest the application of serum cfDNA methylation of OPCML and HOXD9 for differential diagnosis of CCA and other biliary diseases due to its less invasiveness and clinically practical method which may benefit the patients by preventing the misdiagnosis of CCA and avoiding unnecessary surgical intervention. Electronic supplementary material The online version of this article (10.1186/s13148-019-0634-0) contains supplementary material, which is available to authorized users.

BACKGROUND: Cholangiocarcinoma (CCA) is a fatal liver cancer arising from bile duct epithelium. Polycomb repressive complex 2 (PRC2) is a histone methyltransferase enzyme that catalyzes trimethylation of histone H3 on lysine 27, resulting transcriptional gene silencing. The key components of PRC2 are EZH2, SUZ12 and EED, which EZH2 is a catalytic subunit. The defect of individual PRC2 components has been shown to enhance carcinogenesis and cancer progression. We aimed to determine the expression of individual PRC2 components and evaluate its association with clinicopathological data in CCA patients. METHODS: The expression of individual PRC2 components including EZH2, SUZ12 and EED was determined by immunohistochemistry in 40 CCA tissue samples. RESULTS: We found that the expression of EZH2 and SUZ12 in CCA tissue was significantly higher than that in adjacent non-cancerous tissue (P

Figure S1. The optimization of OPCML MS-HRM assay using standard serial dilution series (0–100% methylation). Figure S2. The optimization of HOXA9 MS-HRM assay using standard serial dilution series (0–100% methylation). Figure S3. The optimization of HOXD9 MS-HRM assay using standard serial dilution series (0–100% methylation). Figure S4. Scatter plots of OPCML, HOXA9 and HOXD9 methylation in serum cfDNA between intrahepatic and extrahepatic CCA patients. Table S1. The association of OPCML and HOXD9 methylation with clinicopathological data. (PDF 1317 kb)