Differences Of Clinicopathological Features And Gene Expression Profiles In Centrally Located Hepatocellular Carcinoma Of High Risk Recurrence Group

This MD degree project is composed of two parts.Part Ⅰ. Analysis of Prognostic Factors for Centrally Located Hepatocellular Carcinoma:High risk, Mid risk, and Low riskA pilot study in a single Chinese instituteObjective:Reports on the clinical features and prognosis of patients after liver resection for centrally located hepatocellular carcinoma (cHCC) are lacking. This study aimed to clarify the prognostic risk factors for cHCC in a cohort of Chinese patients.Methods:We retrospectively reviewed the data from 173 patients who underwent hepatectomy for cHCC in Chinese National Cancer Center from October 2006 to January 2013. We divided patients into three subgroups according to disease-free survival (DFS): high risk (DFS≤1 years), mid risk (1 years<DFS≤3 years), and low risk (DFS>3 years). Clinicopathological characteristics were compared and prognostic factors were evaluated using univariate and multivariate analyses.Results:Among all the patients reviewed,74 patients were enrolled in the high risk group,67 in the mid risk group, and 32 in the low risk group. The median overall survival (OS) for high risk group was 13.5 months compared to 24.0 months for mid risk group and 45.5 months for low risk group (P= 0.000/0.000). Univariate analysis identified 9 risk factors for all the cases. When separatedly analyzed,68.0% patients of high risk group had risk factors≥ 4.73.1% patients of mid risk group had 2≤risk factors≤ 4 and 78.1% patients of low risk group had risk factors≤ 3. Multivariate analysis among high risk, mid risk and low risk groups demonstrated that tumors adjacent (<1cm) to major vascular trunks and tumor invasive growth were independent prognostic factors for both DFS and OS.40.5% patients of high risk group had both the two risk factors, the percentage was 13.4% in mid risk group and 3.1% in low risk group respectively (P=0.001). A combined model that included all 9 risk factors had higher accuracy in predicting whether belonging to high risk group. In addition, high risk group was correlated with a significantly higher incidence of tumors adjacent (<1cm) to the inferior vena cava compared with the other two groups (21.6 vs.11.9 and 3.1%, P=0.023).Conclusion:Patients of high risk group had more risk factors than those of mid and low risk groups. A prognostic model containing these factors may provide accurate prediction of survival or risk stratification, and cHCC patients with these risk factors should be candidates for adjuvant therapy.Part Ⅱ. Differences of mRNA expression profiles of centrally located hepatocellular carcinoma in high risk groupObjective:The discrepancy of clinical feature and prognostic characteristics is relative large between different individuals. The objective of this study was to compare gene expression profiles among different risk cHCC groups to find some potential molecular markers for cHCC prognosis.Methods:We retrospectively selected 8 samples of high risk group,10 samples of mid risk group and 15 samples of low risk group. The analysis of mRNA expression was performed by Agilent(?) Whole Human Genome Oligo Microarray. Several differentially expressed genes were further analyzed and verified by real time PCR and ELISA.Results:438 differentially expressed genes in the three subgroups were identified through principal component analysis. Cluster analysis demonstrated that 236 up-regulated genes were found to be involved in signal conduction in extracell matrix and immunology, whereas 202 down-regulated genes involved in metabolism. The expressive abundance of differential genes is significantly different between high risk group and low risk group (P<0.05). Six genes including IFNGR1, LAMB3, MFSD2A, RASD1, STARD5, and TRIM35 was validated by real time PCR in 93 HCC samples. The results showed that 93 samples can be divided into high expression group (n=59) and low expression group (n=34) by six genes in combination. Log-rank analysis showed that the DFS in high expression group was significantly worse than low expression group (P=0.024). Plasma MFSD2A level in 109 HCC was significantly higher than that in healthy people (P<0.001). Furthermore, the DFS in HCC patients of high plasma MFSD2A (≥16.382 ng/ml) was significantly shorter than those of low plasma MFSD2A (<16.382 ng/ml) (P=0.037).Conclusion:This study compared mRNA expression among different risk cHCC groups and found some potential differential genes and protein for cHCC recurrence. Which might provide new insights into the molecular mechanisms and prognostic model.