Detection of Aberrantp16^INK4AMethylation in Sera of Patients with Liver Cirrhosis and Hepatocellular Carcinoma

Abstract

Hepatocellular carcinomas (HCCs) show genomic alterations, including DNA rearrangements associated with HBV DNA integration, loss of heterozygosity, and chromosomal amplification. The genes most frequently involved are those encoding tumor suppressors. The p16INK4A tumor suppressor gene frequently displays genetic alteration in HCC tissues. The present study was performed to examine the incidence of methylated p16INK4A in the sera of liver cirrhosis (LC) and HCC patients, and to evaluate its role as a tumor marker of HCC. The sera of 23 LC patients and 46 HCC patients were examined in this study. The methylation status of p16INK4A was evaluated by methylation-specific PCR of serum samples. Methylated p16INK4A was detected in 17.4% (4/23) of LC patients and in 47.8% (22/46) of HCC patients. No association was demonstrated between p16INK4A methylation and serum AFP level. As the status of p16INK4A methylation was not associated with serum AFP level, it may have a role as a tumor marker of HCC.

Predicting Hepatocellular Carcinoma by Detection of Aberrant Promoter Methylation in Serum DNA

“…Wong et al (18) reported a good correlation between p16 hypermethylation in HCC tissues and plasma/ serum DNA (72%) and that p16 hypermethylation was not detected in the plasma/serum of patients with either liver cirrhosis or hepatitis. However, in another study, 17% of cirrhosis patients had serum DNA with aberrant p16 methylation (22). These differing results may be due to the lack of standardized processing of blood samples and methods of analysis; the relatively small sample size and diversity in the clinical courses of patients may also contribute to the variation.…”

“…Another possibility was that some ''normal controls'' have cryptogenic hepatic cirrhosis. A small percentage of patients with liver cirrhosis were reported to be positive for p16 methylation in serum DNA (22), but these changes still need further study. In the present study, the 50 cases were randomly selected.…”

Gene Expression Analysis in HBV Transgenic Mouse Liver: A Model to Study Early Events Related to Hepatocarcinogenesis

“…Recent studies have identified numerous epigenetic changes, such as promoter CpG island methylation, that are responsible for inactivation of tumor suppressor genes (38)(39)(40)(41). Gene expression profiles of HCCs with different etiology show different molecular signatures (42,43), suggesting that heterogeneous hepatocarcinogenetic pathways, involved in cell proliferation, cell cycle, apoptosis, and angiogenesis, exist and are deregulated in hepatocarcinogenesis.…”

Identification and Validation of Colorectal Neoplasia–Specific Methylation Markers for Accurate Classification of Disease

“…As a result, many of these most widely investigated markers are not suitable for specific detection of a particular disease. For example, methylation of the gene CDKN2a (p16) has been reported to be found in blood from patients with numerous types of cancer including oral cancer, gastric cancer, melanoma, nonsmall-cell lung cancer, hepatocellular cancer, and bladder cancer in a number of independent studies (17)(18)(19)(20)(21)(22). Clearly, methylation of this gene is important in neoplastic progression, but its usefulness as a specific marker for a single cancer in a screening application is questionable.…”

“…Clearly, methylation of this gene is important in neoplastic progression, but its usefulness as a specific marker for a single cancer in a screening application is questionable. Furthermore, CDKN2a has been shown to be methylated in blood from individuals with noncancerous diseases, albeit at a lower rate (21,23).…”