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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 4/2015

01-04-2015 | Gastrointestinal Oncology

LINE-1 Methylation Level and Patient Prognosis in a Database of 208 Hepatocellular Carcinomas

Authors: Kazuto Harada, MD, Yoshifumi Baba, MD, PhD, Takatsugu Ishimoto, MD, PhD, Akira Chikamoto, MD, Keisuke Kosumi, MD, Hiromitsu Hayashi, MD, PhD, Hidetoshi Nitta, MD, PhD, Daisuke Hashimoto, MD, PhD, Toru Beppu, MD, PhD, Hideo Baba, MD, PhD

Published in: Annals of Surgical Oncology | Issue 4/2015

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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.
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Metadata
Title
LINE-1 Methylation Level and Patient Prognosis in a Database of 208 Hepatocellular Carcinomas
Authors
Kazuto Harada, MD
Yoshifumi Baba, MD, PhD
Takatsugu Ishimoto, MD, PhD
Akira Chikamoto, MD
Keisuke Kosumi, MD
Hiromitsu Hayashi, MD, PhD
Hidetoshi Nitta, MD, PhD
Daisuke Hashimoto, MD, PhD
Toru Beppu, MD, PhD
Hideo Baba, MD, PhD
Publication date
01-04-2015
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue 4/2015
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-4134-3

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