Non-invasive detection of biliary tract cancer by low-coverage whole genome sequencing from plasma cell-free DNA: A prospective cohort study
Xiang Wang, Xiaohui Fu, Ziliang Qian, Teng Zhao, Anqi Duan, Xiang Ruan, Bin Zhu, Lei Yin, Yongjie Zhang, Wenlong Yu
Abstract
The diagnosis of biliary tract cancer (BTC) is challenging in clinical practice. We performed a prospective study to evaluate the value of plasma copy number variation (CNV) assays in diagnosing BTC. 47 treatment-naïve patients with suspicious biliary lesions were recruited. Plasma samples were collected at admission. Cell-free DNA was analyzed by low coverage whole genome sequencing, followed by CNV analyses via a customized bioinformatics workflow, namely the ultrasensitive chromosomal aneuploidy detector. 29 patients were pathologically diagnosed as BTC, including 8 gallbladder cancers (GBCs) and 21 cholangiocarcinomas (CCs). Cancer patients had more CNV signals as compared with benign patients (26/29 vs. 2/18, P < 0.001). The most frequent copy number gains were chr3q (7/29) and chr8q (6/29). The most frequent copy number losses were chr7p (6/29), chr17p (6/29), and chr19p (6/29). The sensitivity and specificity of plasma CNV assays in diagnosing BTC were 89.7% and 88.9%, respectively. For CA 19-9 (cutoff: 37 U/ml), the sensitivity was 58.6% and the specificity was 72.2%. The diagnostic accuracy of CNV assays significantly outperformed CA 19-9 (AUC 0.91 vs. 0.62, P = 0.004). Compared with CA 19-9 alone, the adding of CNV profiles to CA 19-9 increased the sensitivity in diagnosing GBC (75.0% vs. 25.0%) and CC (100% vs. 52.4%). Higher CNV burden was also associated with decreased overall survival (Hazard ratio = 4.32, 95% CI 2.06–9.08, P = 0.033). Our results suggest that BTC harbors rich plasma CNV signals, and their assays might be useful for diagnosing BTC.