Diagnostic and Prognostic Value of Circulating Cell-Free DNA for Cholangiocarcinoma

Abstract

The analysis of cfDNA has been applied as a liquid biopsy in several malignancies. However, its value in the diagnosis and prognosis of cholangiocarcinoma (CCA) have not been well defined. We aimed to investigate the diagnostic and prognostic values of cfDNA level and tumor-specific mutation in circulating DNA (ctDNA) in CCA. The plasma cfDNA levels from 62 CCA patients, 33 benign biliary disease (BBD) patients and 30 normal controls were quantified by fluorescent assay. Targeted probe-based sequencing of 60 genes was applied for mutation profiling in 10 ctDNA samples and their corresponding treatment-naïve tissues. cfDNA levels in CCA were significantly higher than those in BBD and normal controls. We found that cfDNA levels at 0.2175 and 0.3388 ng/µL significantly discriminated CCA from healthy controls and BBD with 88.7 and 82.3% sensitivity and 96.7 and 57.6% specificity, respectively. cfDNA levels showed superior diagnostic efficacy in detecting CCA compared to CEA and CA19-9. ARID1A (30%), PBRM1 (30%), MTOR (30%), and FGFR3 (30%) mutations were the most common. Using nine frequently mutated genes in the ctDNA samples, the diagnostic accuracy of cfDNA sequencing was 90.8%, with 96.7% average sensitivity and 72.4% specificity. This study supports the use of cfDNA as a diagnosis and prognostic biomarker for CCA.

Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review

“…Yang et al [ 113 ] showed that CTCs were associated with more-aggressive tumour characteristics and were independently associated with a poorer survival in patients with cholangiocarcinoma. Wintachai et al [ 114 ] investigated the diagnostic and prognostic values of plasma cfDNA levels from 62 cholangiocarcinoma patients, 33 benign biliary disease patients and 30 normal controls. They demonstrated a superior diagnostic efficacy of cfDNA in detecting cholangiocarcinoma than CEA and CA19-9.…”

Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance

“…Additional prognostic biomarkers might enable more accurate patient risk assessment and stratification in clinical trials. Predictive biomarkers for selecting the optimal therapy, such as circulating tumour DNA-based assays for FGFR2 fusions and IDH1 mutations 176,177 , are already in clinical use and will push the field forward. Finally, additional pharmacodynamic biomarkers capable of tracking disease evolution more accurately than the carbohydrate antigen 19-9 (CA 19-9), which is a tumour marker used in the management of biliary and pancreatic cancer, and that can reveal the emergence of drug resistance are warranted 178 , as shown for resistance to FGFR2 inhibitors 179 .…”

Pushing the limits for the surgical treatment of intrahepatic cholangiocarcinoma

“…We do agree, however, on its value as another tool to monitor treatment response and relapse post-surgical resection. Soon, circulating-tumor DNA (ctDNA) may become the tumor marker of choice, as the ctDNA level showed up to 89% sensitivity and 97% specificity to diagnose CCAs, outperforming both CA19-9 and CEA ( 7 ). Further research is on its way to determine the impact of liquid biopsy in this setting.…”