Molecular differences between AFP-negative and AFP-positive hepatocellular carcinoma.

Abstract

e15681 Background: Alpha-fetoprotein (AFP) is a major biomarker for diagnosis of hepatocellular carcinoma (HCC). Screening of molecular differences between AFP-negative and AFP-positive HCC can be helpful for its diagnosis. Methods: Genomic mutations, gene expressions and clinicopathological data of 270 HCC patients were collected from TCGA database. According to preoperative AFP level, patients were categorized into AFP- (0-20ng/mL, n = 112) and AFP+ ( > 20 ng/mL, n = 158) groups. We identified significantly mutated genes and differentially expressed genes (DEGs) between the two groups and analyzed their correlation with prognosis. Results: The 1-, 3-, and 5-year overall survival (OS) rates were 91.5%, 76.3%, and 67.9% in AFP- and 84.3%, 62.5%, and 34.2% in AFP+. The difference was statistically significant (p = 0.0053). To identify AFP-biased mutation genes, we focused on highly mutated genes in each group (≥5% mutation frequency). At FDR = 0.05, we identified 11 AFP-biased genes: CTNNB1, VWA5B2, HERC2, ZFYVE26, SPEN, MUC6, DST, WDR87, DNAH1, PTPN13, and FANCM. The most striking gene identified was CTNNB1, which is a WNT pathway oncogene. CTNNB1 was more frequently mutated in AFP- than in AFP+ (35.8% vs. 17.0%, p = 0.00059). The OS for HCC was calculated on the basis of the mutation of each gene, which showed that MUC6 mutation was negatively associated with OS (p = 0.018), while other ten genes showed no obvious difference. With the mRNA expression data, a total of 949 DEGs were identified, consisting of 718 upregulated in AFP+, and 231 upregulated in AFP-. The enriched pathways of the DEGs included cell cycle, metabolism of xenobiotics by cytochrome P450 and chemical carcinogenesis. AVP, CCL20 and MUC6 genes were identified as hub genes in the PPI network. Conclusions: According to the results of this study, the AFP level is associated with patients’ OS rates, and AFP- patients tend to have higher CCTNB1 mutation rate. Our ongoing study will verify this result by enrolling new HCC patients.