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.
SummaryBiliary 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.
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.
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<0.001). Furthermore, high AXL expression was significantly associated with lymph node metastasis (p=0.035). Interestingly, patients with combined low OPCML/high AXL expression had significantly shorter overall survival (p=0.007). OPCML enhanced the effect of AXL inhibitor R428 in AXL-expressing CCA cell lines. Conclusion: Combined expression of OPCML and AXL shows potential value as a prognostic marker and OPCML as an agent enhancing the effect of R428 may contribute to better prognosis for patients with CCA.Cholangiocarcinoma (CCA) is a malignancy that arises from bile duct epithelial cells (1). CCA is rare worldwide but common in Southeast Asia, particularly in Northeastern Thailand, and is related to liver fluke (Opisthorchis viverrini) infection, which is known to be a strong risk factor for CCA in this region (2). Nowadays, CCA accounts for about 2% of cancer-related deaths per year worldwide. Moreover, it is characterized by a poor prognosis due to a lack of early detection and its low response rate to existing chemotherapy (3). Accordingly, it is crucial to find out novel biomarkers and therapeutic strategies to improve CCA prognosis.Opioid-binding protein/cell adhesion molecule-like (OPCML) is a glycosyl phosphatidylinositol-anchored cell adhesion-like molecule which belongs to a member of the IgLON subfamily in the immunoglobulin superfamily of cell adhesion molecules of proteins (4). Normally, OPCML plays roles in a cell adhesion and is a negative regulator. Moreover, OPCML also acts as a tumor suppressor which is often inactivated by DNA hypermethylation, resulting in gene silencing in several cancer types (5-8), including CCA (9).Previous studies revealed the crucial functions of OPCML in the inhibition of progression of many types of human 1168
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.
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