Development and Validation of a New Tumor-Based Gene Signature Predicting Prognosis of HBV/HCV-Included Resected Hepatocellular Carcinoma Patients

Background: Due to the phenotypic and molecular diversity of hepatocellular carcinomas (HCC), it is a challenge to determine patients' prognosis. We intent to identify new biomarkers of resected patients. Methods: 274 HCC samples from patients at Zhongshan hospital, Fudan university were collected. Gene expression analyses were performed using NanoString technology and compared with patient survival information. We identified a "9-gene signature" associated with survival by using the coefficient and regression formula of multivariate Cox model. This molecular signature was then validated in three patients cohorts from internal cohort (n=69), TCGA dataset (n=369) and HCC genomic consortium (n=80). Results: We identified 9-gene signature consisting of ZC2HC1A, MARCKSL1, PTGS1, CDKN2B, CLEC10A, PRDX3, PRKCH, MPEG1 and LMO2. The 9-gene signature was used, combined with clinical parameters, to fit a multivariable Cox model to the training data (concordance index, ci=0.85), which was successfully validated (ci=0.86 for internal cohort; ci=0.78 for external cohort). The signature showed improved performance compared with clinical parameters alone (ci=0.70). Furthermore, the signature predicted patient prognosis than previous gene signatures more accurately. It was also used to stratify early-stage, HBV or HCV-infected patients into groups with low and high risk of survival, leading to significant differences in survival in training and validation (P<0.001). Conclusions: The 9-gene signature is associated with clinical outcomes with resected HCC or receiving adjuvant transarterial chemoembolization in different clinical settings, especially in early stage disease. This new signature should be validated in prospective studies to stratify patients in clinical decisions. Funding Statement: This work was supported by the National Natural Science Fund of China (Grant numbers: No. 81672330; No. 81472218). Declaration of Interests: All authors: no conflicts. Ethics Approval Statement: This study was approved by our institutional review boards of Zhongshan hospital of Fudan university, and informed consent was obtained from all study participants.