title: LINE-1 hypomethylation, DNA copy number alterations, and CDK6 amplification in esophageal squamous cell carcinoma.
abstract: OBJECTIVE
  Global DNA hypomethylation plays a crucial role in genomic instability and carcinogenesis. DNA methylation of the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level, and is attracting interest as a useful marker for predicting cancer prognosis. Our previous study using more than 200 esophageal squamous cell carcinoma (ESCC) specimens demonstrated the significant relationship between LINE-1 hypomethylation and poor prognosis. However, the mechanism by which LINE-1 hypomethylation affects aggressive tumor behavior has yet to be revealed.
  
  
  METHODS
  To examine the relationship between LINE-1 hypomethylation and DNA copy number variations, we investigated LINE-1-hypomethylated and LINE-1-hypermethylated ESCC tumors by comparative genomic hybridization array.
  
  
  RESULTS
  LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6. LINE-1 methylation levels were significantly associated with CDK6 mRNA and CDK6 protein expression levels in ESCC specimens. In our cohort of 129 patients with ESCC, cases with CDK6-positive expression experienced worse clinical outcome compared with those with CDK6-negative expression, supporting the oncogenic role of CDK6 in ESCC. In addition, we found that the prognostic impact of LINE-1 hypomethylation might be attenuated by CDK6 expression.
  
  
  CONCLUSIONS
  LINE-1 hypomethylation (i.e., global DNA hypomethylation) in ESCC might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as CDK6.
authors.affiliation: Authors' Affiliations: Department of Gastroenterological Surgery, Graduate School of Medical Sciences; Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka; and Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Asuka
authors.initials: A
authors.lastname: Murata
authors.forename: Hironobu
authors.initials: H
authors.lastname: Shigaki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: Shiro
authors.initials: S
authors.lastname: Iwagami
authors.forename: Naoya
authors.initials: N
authors.lastname: Yoshida
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sakamaki
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D008297:Male; D011379:Prognosis
chemical_list: D019938:Cyclin D1; D051361:Cyclin-Dependent Kinase 6