title: 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.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Harada
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Akira
authors.initials: A
authors.lastname: Chikamoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kosumi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hayashi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nitta
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hashimoto
authors.forename: Toru
authors.initials: T
authors.lastname: Beppu
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D019175:DNA Methylation; D016208:Databases, Factual; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6