CpG Island Methylator Phenotype Association with Elevated Serum α-Fetoprotein Level in Hepatocellular Carcinoma

Purpose: CpG island methylator phenotype (CIMP) involves hypermethylation targeted toward the promoters of multiple genes. To gain insight into the role of epigenetic aberration of tumor-related genes in hepatocarcinogenesis, we determined a hypermethylation profile in hepatocellular carcinoma (HCC). Experimental Design: We examined the promoter methylation status of nine genes in 50 HCCs, 50 paired nontumor tissues, and 6 normal liver tissues by methylation-specific PCR. CIMP+ was defined as having five genes that are concordantly methylated. Results: The frequency of promoter methylation of nine genes in 50 HCCs varied from 10% in P53 to 94% in c-Myc . The methylation status of P14, P15, P16, ER, RASSF1A, WT1 , and c-Myc was significantly correlated with HCC and nontumor tissues ( P < 0.05). Hypermethylation of one or more genes was found in 96% of HCC. CIMP was more frequent in HCC than in nontumor tissues (70% and 12%, P < 0.001). There is a significant association between CIMP and methylation of P14, P15, P16, ER, RSAAF1A , and WT1 ( P < 0.05) and serum α-fetoprotein (AFP) level ( P = 0.017). CIMP+ was more frequent in HCC with AFP ≥ 30 μg/L than those with AFP < 30 μg/L ( P = 0.005). In addition, the promoter hypermethylation of P15 and P16 was associated with elevated serum AFP levels in 35 HCC samples with CIMP+ ( P < 0.05). Conclusions: Positive correlation of CIMP and AFP levels in HCC suggests that CIMP can serve as a molecular marker of late-stage HCC development.