CpG island methylator phenotype association with elevated serum alpha-fetoprotein level in hepatocellular carcinoma.
OBJECTIVE
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).


METHODS
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 alpha-fetoprotein (AFP) level (P=0.017). CIMP+ was more frequent in HCC with AFP>or=30 microg/L than those with AFP<30 microg/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.
Zhang
Changsong
C
Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Li
Zhengyou
Z
Cheng
Yue
Y
Jia
Fengqi
F
Li
Rong
R
Wu
Mengchao
M
Li
Ke
K
Wei
Lixin
L
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011401:Promoter Regions, Genetic; D000509:alpha-Fetoproteins / Q000096:biosynthesis*
D017931:DNA Primers; D000509:alpha-Fetoproteins