|Title:||High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma||Authors:||PO-HUANG LEE||Issue Date:||2002||Journal Volume:||35||Journal Issue:||2||Start page/Pages:||85-92||Source:||Molecular Carcinogenesis||Abstract:||
Epigenetic changes in gene expression due to extensive CpG island methylation is now accepted as the main cause of inactivation of the p16 gene. More recently, it has been suggested that the human ras association domain family (RASSF) 1 gene, cloned from the lung tumor-suppressor locus 3p21.3, also may be inactivated by methylation. It consists of two major alternative transcripts, RASSF1A and RASSF1C. Epigenetic inactivation of isoform A was observed in several carcinomas and tumor cell lines. In this study, promoter hypermethylation of RASSF1A and p16 was investigated in 83 hepatocellular carcinoma (HCC) tissue samples from Taiwan and in two HCC cell lines (Hep3B and HepG2). High frequencies (85% and 47%, respectively) of methylation of the CpG island promoters of RASSF1A and p16 were found in the HCC tissues. The methylation of RASSF1A also was detected in Hep3B cells but not in HepG2 cells; p16 was not methylated in either cell line. Methylation status was determined in 12 normal control liver tissues and 10 adjacent nontumor tissues. No methylation was found in normal liver control tissues for both RASSF1A and p16; methylation was detected in one of 10 and seven of 10 adjacent nontumor tissue sampless for p16 and RASSF1A, respectively, in subjects with positive tumors. These data indicate that aberrant methylation of the CpG island promoters of both genes is a frequent occurrence in hepatocarcinogenesis. The high frequency of RASSF1A methylation in adjacent tissues suggests that this may be an early event. The relationship between methylation status and clinical parameters and tumor markers, including DNA damage resulting from aflatoxin B1 (AFB1), an environmental carcinogen, and p53 status, also was analyzed. A statistically significant association was found between RASSF1A methylation status and the level of AFB1-DNA adducts in tumor tissues. No association was found between methylation status and p53 status. These results suggest the hypothesis that exposure to environmental carcinogens may be involved in altered methylation of genes involved in cancer development. ? 2002 Wiley-Liss, Inc.
|DOI:||10.1002/mc.10076||SDG/Keyword:||aflatoxin B1; carcinogen; article; cancer genetics; cell strain HepG2; chemical carcinogenesis; controlled study; CpG island; DNA adduct; DNA damage; DNA methylation; environmental exposure; female; gene; gene expression; gene inactivation; gene locus; human; human cell; human tissue; liver carcinogenesis; liver cell carcinoma; major clinical study; male; molecular cloning; multigene family; p16 gene; priority journal; promoter region; rassf1a gene; statistical significance; Aflatoxin B1; Alternative Splicing; Carcinoma, Hepatocellular; Chromosomes, Human, Pair 3; CpG Islands; Cyclin-Dependent Kinase Inhibitor p16; DNA Adducts; DNA Methylation; Female; Genes, Tumor Suppressor; Hela Cells; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Proteins; Promoter Regions (Genetics); Protein Isoforms; Tumor Suppressor Protein p53; Tumor Suppressor Proteins
|Appears in Collections:||醫學系|
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