Non-invasive diagnosis of esophageal cancer by a simplified circulating cell-free DNA methylation assay targeting OTOP2 and KCNA3: a double-blinded, multicenter, prospective study

• Published in: Journal of hematology and oncology Vol. 17; no. 1; pp. 47 - 6
• Main Authors: Bian, Yan, Gao, Ye, Lin, Han, Sun, Chang, Wang, Wei, Sun, Siyu, Li, Xiuling, Feng, Zhijie, Ren, Jianlin, Chen, Hezhong, Lu, Chaojing, Xu, Jinfang, Zhou, Jun, Wan, Kangkang, Xin, Lei, Li, Zhaoshen, Wang, Luowei
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 18.06.2024; BioMed Central; BMC
• Subjects: Accuracy; Adult; Aged; Algorithms; Biomarkers; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Biopsy; Cancer; Cell-free DNA; Cell-Free Nucleic Acids - blood; Correspondence; Diagnosis; Diagnostic equipment (Medical); Digestive system; DNA; DNA Methylation; Double-Blind Method; Esophageal cancer; Esophageal Neoplasms - blood; Esophageal Neoplasms - diagnosis; Esophageal Neoplasms - genetics; Esophagus; Female; Genetic aspects; Genetic research; Genomes; Humans; Liquid biopsy; Male; Malignancy; Medical prognosis; Methylation; MicroRNAs; Middle Aged; Noninvasive detection; Oncology, Experimental; Peripheral blood; Plasma; Prospective Studies; Sensitivity analysis; Squamous cell carcinoma; Taiwan; China; Cell-free DNA; Liquid biopsy; Methylation; Noninvasive detection; Esophageal cancer
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-024-01565-2

Esophageal cancer (EC) is a highly lethal disease lacking early detection approaches. We previously identified that OTOP2 and KCNA3 were specifically hypermethylated in circulating cell-free DNA from patients with EC. We then developed a blood-based methylation assay targeting OTOP2 and KCNA3 (named "IEsohunter") for esophageal cancer noninvasive detection. This double-blinded, multicenter, prospective study aimed to comprehensively evaluate its clinical diagnostic performance. Participants with EC, high-grade intraepithelial neoplasia (HGIN), other malignancies, benign gastrointestinal lesions, or no abnormalities were prospectively enrolled from 5 tertiary referral centers across China. Peripheral blood samples were collected, followed by plasma cell-free DNA methylation analysis using the IEsohunter test based on multiplex quantitative polymerase chain reaction adopting an algorithm-free interpretation strategy. The primary outcome was the diagnostic accuracy of IEsohunter test for EC. We prospectively enrolled 1116 participants, including 334 patients with EC, 71 with HGIN, and 711 controls. The areas under the receiver operating characteristic curves of the IEsohunter test for detecting EC and HGIN were 0.903 (95% CI 0.880-0.927) and 0.727 (95% CI 0.653-0.801), respectively. IEsohunter test showed sensitivities of 78.5% (95% CI 69.1-85.6), 87.3% (95% CI 79.4-92.4), 92.5% (95% CI 85.9-96.2), and 96.9% (95% CI 84.3-99.8) for stage I-IV EC, respectively, with an overall sensitivity of 87.4% (95% CI 83.4-90.6) and specificity of 93.3% (95% CI 91.2-94.9) for EC detection. The IEsohunter test status turned negative (100.0%, 47/47) after surgical resection of EC. The IEsohunter test showed high diagnostic accuracy for EC detection, indicating that it could potentially serve as a tool for noninvasive early detection and surveillance of EC.