Differences Of Clinicopathological Features And Gene Expression Profiles Between Alpha-fetoprotein Negative And Positive Hepatocellular Carcinoma

This MD degree project is composed of two parts.Part Ⅰ. Differences of clinicopathological features and prognosis between alpha-fetoprotein negative and positive hepatocellular carcinomaObjective:To investigate the prognosis significance of preoperative serum alpha-fetoprotein (AFP) and the correlation with clinicopathological factors of hepatocellular carcinoma (HCC) patients who underwent hepatectomy.Methods:Clinicopathological data of retrospective analysis was performed on 251 HCC patients that underwent hepatectomy in this study. According to preoperative AFP level, patients were categorized into AFP negative group (0-20ng/mL) and AFP positive group (> 20ng/mL) for Kaplan-Meier analysis and Cox proportional hazards regression models.Results:The results demonstrated that increased AFP exhibited characteristics of longer prothrombin time (PT), liver capsule invasion, low grade differentiation, and late Barcelona Clinic Liver Center (BCLC) stage. Moreover, the female patients had a greater prevalence of increased preoperative AFP than male patients [284.8(3.975-3167.5) vs (3.653-140.65); Z-2.895, P=0.004]. The 1-,3-, and 5-year recurrence free survival (RFS) rates were 78.1,57.5, and 40.6% in the AFP negative group and 61.8,37.7, and 31.4%, respectively, in the AFP positive group (Log rank test 8.312, P=0.004). The 1-,3-, and 5-year overall survival (OS) rates were 94.4,83.8, and 62.3% in the AFP negative group and 87.2,60.0, and 36.7%, respectively, in the AFP positive group. The difference was statistically significant (Log rank test,16.884, P< 0.000). Cox proportional hazards model identified preoperative AFP as independent prognostic predictors of survival.Conclusion:The AFP positive group exhibited characteristics of more malignant tumor biological behavior than the AFP negative group. The female patients had a higher preoperative AFP than male patients. Preoperative serum AFP is an important predictor of prognosis among HCC patients following surgical resection.Part Ⅱ. Differences of mRNA expression profiles between alpha-fetoprotein negative and positive hepatocellular carcinomaObjective:HCC is a heterogeneous disease with different genetic profiles and clinical outcomes. The aim of the study was to compare gene expression profiles between AFP negative and AFP positive HCC to find the molecular differences among the two groups and some potential molecular markers for HCC diagnosis and prognosis.Methods:The analysis of mRNA expression was performed on 20 samples of AFP negative and 20 samples of AFP positive HCC associated with HBV infection through Agilent(?) Whole Human Genome Oligo Microarray. Bioinformatics analyses were used to identify genes and pathways. Some differently expressed genes were further analyzed by real time PCR and/or ELISA.Results:392 differentially expressed genes in the two groups were identified through principal component analysis.62 up-regulated genes in AFP negative HCC were found to be involved in cell apoptosis and programmed cell death, whereas 290 up-regulated genes in AFP positive HCC involved in mitosis and cell cycle. It was validated by real time PCR that LAMB3, MFSD2A, STARD5, and TRIM35 were higher expressed in AFP negative HCC than those in AFP positive HCC. Plasma MFSD2A level in HCC was significantly higher than that in healthy people, and it had a good performance in HCC diagnosis with AUC of 0.8353, sensitivity of 74.16% and specificity of 89.47%. Furthermore, plasma MFSD2A could improve the identification of AFP negative HCC with AUC of 0.8305, sensitivity of 71.15% and specificity of 89.47%. Plasma MFSD2A is a potential diagnostic marker for HCC, especially for AFP negative HCC.Conclusion:This study suggests some potential novel diagnostic markers for HCC and provides new insights into the molecular mechanisms and novel therapeutic targets of HCC.