Abstract
BackgroundDue to the phenotypic and molecular diversity of hepatocellular carcinomas (HCC), it is still a challenge to determine patients’ prognosis. We aim to identify new prognostic markers for resected HCC patients.Methods274 patients were retrospectively identified and samples collected from Zhongshan hospital, Fudan University. We analyzed the gene expression patterns of tumors and compared expression patterns with patient survival times. 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 (n = 369) and GEO dataset (n = 80).ResultsWe 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 cohort (concordance index, ci = 0.85), which was successfully validated (ci = 0.86 for internal cohort; ci = 0.78 for in silico 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 low and high-risk groups, leading to significant differences in survival in training and validation (P < 0.001).ConclusionsThe 9-gene signature, in which four were upregulated (ZC2HC1A, MARCKSL1, PTGS1, CDKN2B) and five (CLEC10A, PRDX3, PRKCH, MPEG1, LMO2) were downregulated in HCC with poor prognosis, stratified HCC patients into low and high risk group significantly in different clinical settings, including receiving adjuvant transarterial chemoembolization and especially in early stage disease. This new signature should be validated in prospective studies to stratify patients in clinical decisions.
Highlights
Due to the phenotypic and molecular diversity of hepatocellular carcinomas (HCC), it is still a challenge to determine patients’ prognosis
The exclusion items were as follows: tumors has more than 80% of necrosis (34 patients), tumors’ RNA has poor quality or insufficient amount (30 patients), patients was performed with non-curative resection (R1 or R2 resection or extrahepatic metastasis at the time of the surgery) (25 patients), HCC patients were treated by liver transplantation (11 patients), and HCC patients were dying within the first month after liver resection due to surgical complications or decompensated cirrhosis (13 patients)
The diseasefree survival (DFS) was assessed, which was determined by analyzing patients death and censoring patients who suffered from first tumor relapse (When the level of postoperative serum alpha fetoprotein (AFP) was > 20 ng/mL and new focus appeared in the ultrasonic/abdominal computed tomography during follow up, we considered that they had tumor recurrence), tumor-related death or progression
Summary
Due to the phenotypic and molecular diversity of hepatocellular carcinomas (HCC), it is still a challenge to determine patients’ prognosis. It is necessary to investigate patients at high risk for poor clinical outcomes and employed effective therapies to avoid HCC recurrence. Prognosis assessment and decision making after surgery are based on the tumor staging systems (i.e., TNM [4], Japan Integrated Staging [5] and Barcelona Clinic liver cancer [BCLC] [6], cancer of the liver Italian program [7]). They are widely applied to guide treatment therapies or predict HCC clinical outcomes. Some studies have raised to improve the above staging system by introducing tumor characteristics, such as serum alpha fetoprotein (AFP) and pathologic features such as microvascular invasion and tumor differentiation [8, 9]
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