A Panel of Five Plasma Proteins for the Early Diagnosis of Hepatitis B Virus-Related Hepatocellular Carcinoma in Individuals at Risk

Background: Early diagnosis of hepatocellular carcinoma (HCC) improves the long-term survival of patients. Early diagnosis of HCC using alpha fetoprotein (AFP) is ineffective. A combination of biomarkers is reported to detect HCC early. Methods: The study was divided into three stages. In the training stage (Stage I), 19 candidate biomarkers were assayed from the plasma of HCC patients. In the validation stage (Stage II), the effectiveness of the panel of the 5 biomarkers selected in Stage I (P5 panel) for detecting early-stage HCC was tested. Finally, in Stage III, a nested case-control study was set up to evaluate the P5 panel in the preclinical diagnosis of HCC. Between February 2013 and June 2017, we recruited 529 participants to the training stage, 993 participants to the validation stage and 60 participants to the nested case-control study. Findings: A panel of 5 proteins (OPN, GDF15, NSE, TRAP5 and OPG) detected preclinical HCC up to twelve months before clinical diagnosis, which included the use of AFP. For early-stage HCC, the P5 panel showed a high diagnostic accuracy, with AUCs=0.912, 0.918 and 0.881 for the data sets in the training stage, validation cohort 1 and validation cohort 2, respectively. In the nested case-control study, the sensitivity of the P5 panel for diagnosing preclinical HCC increased with time, starting from 12 months before to the time of definitive clinical diagnosis (range, 46.15% to 86. 67%). The AUC values of the P5 panel rose from 0.681 to 0.783 from 12 months to 3 months before the clinical diagnosis of HCC. Interpretation: The P5 panel has the potential to screen populations at high risk of developing HCC and enable the early diagnosis of HCC. Funding Statement: This work was supported by the China National Funds for Distinguished Young Scientists (81425019), the State Key Program of National Natural Science Foundation of China (81730076), Program of Shanghai Academic Research Leader (18XD1405300), the National Natural and the Specially-Appointed Professor Fund of Shanghai (GZ2015009), the Key Project of Natural Science Foundation of China (81730097), the Chang Jiang Scholars Program (2013) of the China Ministry of Education, the National Key Basic Research Program “973 project” (2015CB554000). This work was supported in part by the Grants from the State Key Laboratory of Oncogenes and Related Genes (No.90-17-04). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Approval from the Institutional Ethics Committee at each hospital and written informed consent from each participant were obtained.