Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma

Bin Yang, Mingzhou Guo, James G. Herman, Douglas P. Clark

Research output: Contribution to journalArticle

Abstract

Hepatocellular carcinoma (HCC) is one of the most fatal human malignancies, but the molecular mechanisms of hepatocarcinogenesis remain unclear. Although p53 mutations are frequently observed in Asian HCC, it is not a common event in Western HCC. Recent studies suggest that tumor suppressor genes (TSGs) can also be silenced through epigenetic disruption, such as promoter CpG island methylation, during carcinogenesis. To further understand the molecular mechanism of hepatocarcinogenesis, we have investigated the promoter methylation status of nine TSGs (SOCS-1, GSTP, APC, E-cadherin, RAR-β, p14, p15, p16, and p73) in 51 cases of HCC using methylation-specific polymerase chain reaction. We found that 82% of HCCs had methylation of at least one TSG promoter. The most frequently methylated TSGs in HCC were: SOCS-1 (65%), GSTP (54%), APC (53%), E-cadherin (49%), and p15 (49%). Methylation of SOCS-1, GSTP, APC, E-cadherin, and p15 was more frequent in HCC than in nontumor liver (P <0.05). Methylation of SOCS-1, GSTP, and p15 was also significantly more frequent in HCC than cirrhotic liver (P <0.05). Although methylation of one or two genes could be seen in both nontumor and cirrhotic livers, 53% of the HCC cases had three or more TSG promoters methylated, in comparison to 0% in nontumor liver and 13% in cirrhosis (P = 0.001). Methylation of SOCS-1, APC, and p15 was more frequently seen in hepatitis C virus-positive HCC than hepatitis C virus/hepatitis B virus-negative HCC. Our data suggest that promoter hypermethylation of TSGs is a common event in HCC and may play an important role in hepatocarcinogenesis.

Original languageEnglish (US)
Pages (from-to)1101-1107
Number of pages7
JournalAmerican Journal of Pathology
Volume163
Issue number3
StatePublished - Sep 1 2003

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Tumor Suppressor Genes
Methylation
Hepatocellular Carcinoma
Cadherins
Liver
Hepacivirus
CpG Islands
Hepatitis B virus
Epigenomics
Carcinogenesis
Fibrosis
Polymerase Chain Reaction
Mutation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. / Yang, Bin; Guo, Mingzhou; Herman, James G.; Clark, Douglas P.

In: American Journal of Pathology, Vol. 163, No. 3, 01.09.2003, p. 1101-1107.

Research output: Contribution to journalArticle

Yang, B, Guo, M, Herman, JG & Clark, DP 2003, 'Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma', American Journal of Pathology, vol. 163, no. 3, pp. 1101-1107.
Yang, Bin ; Guo, Mingzhou ; Herman, James G. ; Clark, Douglas P. / Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. In: American Journal of Pathology. 2003 ; Vol. 163, No. 3. pp. 1101-1107.
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abstract = "Hepatocellular carcinoma (HCC) is one of the most fatal human malignancies, but the molecular mechanisms of hepatocarcinogenesis remain unclear. Although p53 mutations are frequently observed in Asian HCC, it is not a common event in Western HCC. Recent studies suggest that tumor suppressor genes (TSGs) can also be silenced through epigenetic disruption, such as promoter CpG island methylation, during carcinogenesis. To further understand the molecular mechanism of hepatocarcinogenesis, we have investigated the promoter methylation status of nine TSGs (SOCS-1, GSTP, APC, E-cadherin, RAR-β, p14, p15, p16, and p73) in 51 cases of HCC using methylation-specific polymerase chain reaction. We found that 82{\%} of HCCs had methylation of at least one TSG promoter. The most frequently methylated TSGs in HCC were: SOCS-1 (65{\%}), GSTP (54{\%}), APC (53{\%}), E-cadherin (49{\%}), and p15 (49{\%}). Methylation of SOCS-1, GSTP, APC, E-cadherin, and p15 was more frequent in HCC than in nontumor liver (P <0.05). Methylation of SOCS-1, GSTP, and p15 was also significantly more frequent in HCC than cirrhotic liver (P <0.05). Although methylation of one or two genes could be seen in both nontumor and cirrhotic livers, 53{\%} of the HCC cases had three or more TSG promoters methylated, in comparison to 0{\%} in nontumor liver and 13{\%} in cirrhosis (P = 0.001). Methylation of SOCS-1, APC, and p15 was more frequently seen in hepatitis C virus-positive HCC than hepatitis C virus/hepatitis B virus-negative HCC. Our data suggest that promoter hypermethylation of TSGs is a common event in HCC and may play an important role in hepatocarcinogenesis.",
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