![]() In DNA from primary CCA tumor tissues, aberrant methylation has been observed in the promoters of tumor-suppressor genes with functional consequences. Food and Drug Administration as part of a multitarget test for screening and early detection of colorectal cancer. ( 12 ) More recently, a stool-based assay of methylated DNA marker (MDM) bone morphogenetic protein 3 ( BMP3) and NDRG4 has been approved by the U.S. ( 10, 11 ) This phenomenon is already known to be broadly informative in cancer for example, as few as four methylated gene promoters can perfectly discriminate tissues of colorectal cancers and adenomas from normal mucosae. Aberrant DNA methylation of cytosine-phosphate-guanidine (CpG) sites within the genome alters gene expression in human cancers. Our group and others have hypothesized that aberrant DNA methylation is a biomarker class that could fill this unmet need. In contrast, the diagnosis of extrahepatic CCA (eCCA), which comprises both perihilar CCA (pCCA) and distal CCA (dCCA), remains difficult, and new modalities to complement imaging and invasive testing are urgently needed. ![]() ( 8 ) Intrahepatic CCA (iCCA) presents on imaging as a liver mass, which can be biopsied. ( 7 ) The mortality benefit of early detection of CCA in patients with PSC by MRI has only recently been demonstrated. #Brush pilot serial serial#( 5, 6 ) Patients with PSC are advised to undergo surveillance for CCA by serial serum carbohydrate antigen 19-9 (CA19-9) and imaging with ultrasound or magnetic resonance imaging (MRI) every 6-12 months. Consequently, the overall 5-year survival of patients with CCA is estimated to be less than 10%. ( 1 ) Unfortunately, CCA is usually diagnosed following symptomatic presentation, which heralds advanced-stage disease, limiting application of curative treatments. ( 2- 5 ) CCA is associated with several established and possible risk factors, including cirrhosis, choledochal cysts, and chronic inflammatory disorders of the biliary tract, especially primary sclerosing cholangitis (PSC) however, most CCAs arise de novo and are considered sporadic. ( 1, 2 ) The overall incidence of CCA appears to have increased over the past three decades. target enrichment long-probe quantitative amplified signalĬholangiocarcinoma (CCA) is an aggressive malignancy that accounts for 10%-15% of all hepatobiliary malignancies.reduced-representation bisulfite sequencing.methylation-specific polymerase chain reaction.Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA. Conclusion: Next-generation DNA sequencing yielded highly discriminant methylation markers for CCA. In the clinical pilot on plasma, a cross-validated recursive partitioning tree prediction model from nine MDMs was accurate for de novo eCCA (AUC, 0.88 ) but not for primary sclerosing cholangitis–associated eCCA (AUC, 0.54 ). In the clinical pilot of 16 MDMs on cytology brushings, methylated EMX1 (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval, 0.95-1.0). From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. 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. 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. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin-fixed, paraffin-embedded CCA tumors and adjacent hepatobiliary control tissues using methylation-specific polymerase chain reaction. Reduced-representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. ![]() Altered DNA methylation markers may improve diagnosis of CCA. Cholangiocarcinoma (CCA) has poor prognosis due to late-stage, symptomatic presentation. ![]()
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