p16INK4A hypermethylation is associated with hepatitis virus infection, age, and gender in hepatocellular carcinoma

Xin Li, Ai Min Hei, Lin Sun, Kiyoshi Hasegawa, Guido Torzilli, Masami Minagawa, Tadatoshi Takayama, Masatoshi Makuuchi

Research output: Contribution to journalArticle

Abstract

Purpose: The tumor suppressor gene p16INK4A is mainly inactivated by an epigenetic change involving promoter hypermethylation in hepatocarcinogenesis. The possible clinical impact of p16INK4A methylation and the potential risk factors for this epigenetic alteration have not been thoroughly investigated. Experimental Design: We studied the methylation status and mRNA and protein expression of p16INK4A in 50 hepatocellular carcinomas and corresponding nonneoplastic liver lesions using methylation-specific PCR, reverse transcription-PCR, and immunohistochemical techniques. Results: p16INK4A hypermethylation was observed in 58% (29 of 50) of the hepatocellular carcinomas and 16% (6 of 38) of the corresponding chronic hepatitis and cirrhosis tissue samples. p16 INK4A methylation was significantly associated with mRNA and protein expression (P <0.001 and P = 0.003, respectively). All of the p16 INK4A-methylated tumors were positive for hepatitis B virus or hepatitis C virus markers, but none of the virus-negative tumors exhibited p16INK4A methylation (P = 0.006). The frequency of p16 INK4A hypermethylation tended to be higher in hepatitis C virus-related tumors (23 of 32, 72%) than in hepatitis B virus-related tumors (6 of 13, 46%; P = 0.1). Aberrant methylation of p16INK4A was also related significantly to increasing age, female gender, and normal levels of serum PIVKA-II (P = 0.02, 0.04, and 0.04, respectively). No statistically significant difference in survival was observed between patients with p16 INK4A hypermethylation and those without. Conclusions: Our observations suggest that p16INK4A hypermethylation may contribute to hepatocarcinogenesis from an early stage and that multiple risk factors, such as viral infections, age, and gender, may be associated with p16INK4A hypermethylation in hepatocarcinogenesis.

Original languageEnglish
Pages (from-to)7484-7489
Number of pages6
JournalClinical Cancer Research
Volume10
Issue number22
DOIs
Publication statusPublished - Dec 15 2004

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Hepatitis Viruses
Cyclin-Dependent Kinase Inhibitor p16
Virus Diseases
Methylation
Hepatocellular Carcinoma
Hepatitis B virus
Epigenomics
Hepacivirus
Neoplasms
Polymerase Chain Reaction
Oncogenic Viruses
Messenger RNA
Chronic Hepatitis
Tumor Suppressor Genes
Reverse Transcription
Fibrosis
Research Design
Survival
Liver
Serum

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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p16INK4A hypermethylation is associated with hepatitis virus infection, age, and gender in hepatocellular carcinoma. / Li, Xin; Hei, Ai Min; Sun, Lin; Hasegawa, Kiyoshi; Torzilli, Guido; Minagawa, Masami; Takayama, Tadatoshi; Makuuchi, Masatoshi.

In: Clinical Cancer Research, Vol. 10, No. 22, 15.12.2004, p. 7484-7489.

Research output: Contribution to journalArticle

Li, Xin ; Hei, Ai Min ; Sun, Lin ; Hasegawa, Kiyoshi ; Torzilli, Guido ; Minagawa, Masami ; Takayama, Tadatoshi ; Makuuchi, Masatoshi. / p16INK4A hypermethylation is associated with hepatitis virus infection, age, and gender in hepatocellular carcinoma. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 22. pp. 7484-7489.
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abstract = "Purpose: The tumor suppressor gene p16INK4A is mainly inactivated by an epigenetic change involving promoter hypermethylation in hepatocarcinogenesis. The possible clinical impact of p16INK4A methylation and the potential risk factors for this epigenetic alteration have not been thoroughly investigated. Experimental Design: We studied the methylation status and mRNA and protein expression of p16INK4A in 50 hepatocellular carcinomas and corresponding nonneoplastic liver lesions using methylation-specific PCR, reverse transcription-PCR, and immunohistochemical techniques. Results: p16INK4A hypermethylation was observed in 58{\%} (29 of 50) of the hepatocellular carcinomas and 16{\%} (6 of 38) of the corresponding chronic hepatitis and cirrhosis tissue samples. p16 INK4A methylation was significantly associated with mRNA and protein expression (P <0.001 and P = 0.003, respectively). All of the p16 INK4A-methylated tumors were positive for hepatitis B virus or hepatitis C virus markers, but none of the virus-negative tumors exhibited p16INK4A methylation (P = 0.006). The frequency of p16 INK4A hypermethylation tended to be higher in hepatitis C virus-related tumors (23 of 32, 72{\%}) than in hepatitis B virus-related tumors (6 of 13, 46{\%}; P = 0.1). Aberrant methylation of p16INK4A was also related significantly to increasing age, female gender, and normal levels of serum PIVKA-II (P = 0.02, 0.04, and 0.04, respectively). No statistically significant difference in survival was observed between patients with p16 INK4A hypermethylation and those without. Conclusions: Our observations suggest that p16INK4A hypermethylation may contribute to hepatocarcinogenesis from an early stage and that multiple risk factors, such as viral infections, age, and gender, may be associated with p16INK4A hypermethylation in hepatocarcinogenesis.",
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T1 - p16INK4A hypermethylation is associated with hepatitis virus infection, age, and gender in hepatocellular carcinoma

AU - Li, Xin

AU - Hei, Ai Min

AU - Sun, Lin

AU - Hasegawa, Kiyoshi

AU - Torzilli, Guido

AU - Minagawa, Masami

AU - Takayama, Tadatoshi

AU - Makuuchi, Masatoshi

PY - 2004/12/15

Y1 - 2004/12/15

N2 - Purpose: The tumor suppressor gene p16INK4A is mainly inactivated by an epigenetic change involving promoter hypermethylation in hepatocarcinogenesis. The possible clinical impact of p16INK4A methylation and the potential risk factors for this epigenetic alteration have not been thoroughly investigated. Experimental Design: We studied the methylation status and mRNA and protein expression of p16INK4A in 50 hepatocellular carcinomas and corresponding nonneoplastic liver lesions using methylation-specific PCR, reverse transcription-PCR, and immunohistochemical techniques. Results: p16INK4A hypermethylation was observed in 58% (29 of 50) of the hepatocellular carcinomas and 16% (6 of 38) of the corresponding chronic hepatitis and cirrhosis tissue samples. p16 INK4A methylation was significantly associated with mRNA and protein expression (P <0.001 and P = 0.003, respectively). All of the p16 INK4A-methylated tumors were positive for hepatitis B virus or hepatitis C virus markers, but none of the virus-negative tumors exhibited p16INK4A methylation (P = 0.006). The frequency of p16 INK4A hypermethylation tended to be higher in hepatitis C virus-related tumors (23 of 32, 72%) than in hepatitis B virus-related tumors (6 of 13, 46%; P = 0.1). Aberrant methylation of p16INK4A was also related significantly to increasing age, female gender, and normal levels of serum PIVKA-II (P = 0.02, 0.04, and 0.04, respectively). No statistically significant difference in survival was observed between patients with p16 INK4A hypermethylation and those without. Conclusions: Our observations suggest that p16INK4A hypermethylation may contribute to hepatocarcinogenesis from an early stage and that multiple risk factors, such as viral infections, age, and gender, may be associated with p16INK4A hypermethylation in hepatocarcinogenesis.

AB - Purpose: The tumor suppressor gene p16INK4A is mainly inactivated by an epigenetic change involving promoter hypermethylation in hepatocarcinogenesis. The possible clinical impact of p16INK4A methylation and the potential risk factors for this epigenetic alteration have not been thoroughly investigated. Experimental Design: We studied the methylation status and mRNA and protein expression of p16INK4A in 50 hepatocellular carcinomas and corresponding nonneoplastic liver lesions using methylation-specific PCR, reverse transcription-PCR, and immunohistochemical techniques. Results: p16INK4A hypermethylation was observed in 58% (29 of 50) of the hepatocellular carcinomas and 16% (6 of 38) of the corresponding chronic hepatitis and cirrhosis tissue samples. p16 INK4A methylation was significantly associated with mRNA and protein expression (P <0.001 and P = 0.003, respectively). All of the p16 INK4A-methylated tumors were positive for hepatitis B virus or hepatitis C virus markers, but none of the virus-negative tumors exhibited p16INK4A methylation (P = 0.006). The frequency of p16 INK4A hypermethylation tended to be higher in hepatitis C virus-related tumors (23 of 32, 72%) than in hepatitis B virus-related tumors (6 of 13, 46%; P = 0.1). Aberrant methylation of p16INK4A was also related significantly to increasing age, female gender, and normal levels of serum PIVKA-II (P = 0.02, 0.04, and 0.04, respectively). No statistically significant difference in survival was observed between patients with p16 INK4A hypermethylation and those without. Conclusions: Our observations suggest that p16INK4A hypermethylation may contribute to hepatocarcinogenesis from an early stage and that multiple risk factors, such as viral infections, age, and gender, may be associated with p16INK4A hypermethylation in hepatocarcinogenesis.

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