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

Authors' Affiliations: ¹ Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; ² Department of Cancer Molecular Epidemiology, Shantou University Medical College, Shantou, Guangdong, China; and ³ Biology College, Shandong Normal University, Jinan, Shandong, China

Requests for reprints: Lixin Wei, Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China. Phone: 86-21-25070855; Fax: 86-21-35030398; E-mail: lixinwei{at}smmu.edu.cn.

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 -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.