LINE-1 methylation level and patient prognosis in a database of 208 hepatocellular carcinomas.

Abstract

BACKGROUND:

The level of long interspersed nucleotide element-1 (LINE-1) methylation has become regarded as a surrogate marker of global DNA methylation. Previously, we demonstrated that LINE-1 hypomethylation might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as cyclin-dependent kinase 6 (CDK6) in esophageal squamous cell carcinoma. However, the relationship between LINE-1 hypomethylation and clinical outcome in hepatocellular carcinoma (HCC) remains unclear.

METHODS:

LINE-1 methylation level in 208 samples of curatively resected HCCs was measured by pyrosequencing assay, and the prognostic value of LINE-1 methylation level in HCC was examined.

RESULTS:

LINE-1 methylation levels in the 208 HCC patients investigated were distributed as follows: mean 64.7; median 64.6; standard deviation (SD) 13.6; range 21.5-99.1; interquartile range 62.9-66.6. Univariate Cox regression analysis revealed a significantly higher cancer recurrence rate in the low-methylation-level group than in the high-methylation-level group (hazard ratio 1.58; 95 % CI 1.05-2.47; p = 0.028). Interestingly, the influence of LINE-1 hypomethylation on patient outcome was modified by hepatitis virus infection (p of interaction = 0.023); LINE-1 hypomethylation was associated with a higher cancer recurrence rate in patients without hepatitis virus infection (log-rank p = 0.0047). CDK6 messenger RNA expression levels were inversely associated with LINE-1 methylation levels (p = 0.0075; R = -0.37).

CONCLUSIONS:

Genome-wide DNA hypomethylation, as measured by LINE-1 levels, might be associated with poor disease-free survival in HCC patients, suggesting a potential role for LINE-1 methylation level as a biomarker for identifying patients who will experience an unfavorable clinical outcome.

• Authors: Kazuto Harada, Yoshifumi Baba, Takatsugu Ishimoto, Akira Chikamoto, Keisuke Kosumi, Hiromitsu Hayashi, Hidetoshi Nitta, Daisuke Hashimoto, Toru Beppu, Hideo Baba
• Journal: Annals of surgical oncology (Ann Surg Oncol) Vol. 22 Issue 4 Pg. 1280-7 (Apr 2015) ISSN: 1534-4681 [Electronic] United States
• PMID: 25319577 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial)

Chemical References

• Biomarkers, Tumor
• RNA, Messenger
• CDK6 protein, human
• Cyclin-Dependent Kinase 6

Topics

• Aged
• Biomarkers, Tumor (genetics)
• Carcinoma, Hepatocellular (genetics, mortality, pathology)
• Case-Control Studies
• Cyclin-Dependent Kinase 6 (genetics)
• DNA Methylation
• Databases, Factual
• Female
• Follow-Up Studies
• Humans
• Liver (metabolism)
• Liver Neoplasms (genetics, mortality, pathology)
• Long Interspersed Nucleotide Elements (genetics)
• Male
• Neoplasm Recurrence, Local (genetics, mortality, pathology)
• Neoplasm Staging
• Prognosis
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate