Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer

Alexandros Daskalos, Georgios Nikolaidis, George Xinarianos, Paraskevi Savvari, Adrian Cassidy, Roubini Zakopoulou, Athanasios Kotsinas, Vassilis Gorgoulis, John K Field, Triantafillos Liloglou

Research output: Contribution to journalArticle (journal)peer-review

236 Citations (Scopus)

Abstract

LINE-1 and Alu elements are non-LTR retrotransposons, constituting together over 30% of the human genome and they are frequently hypomethylated in human tumors. A relationship between global hypomethylation and genomic instability has been shown, however, there is little evidence to suggest active role for hypomethylation-mediated reactivation of retroelements in human cancer. In our study, we examined by Pyrosequencing the methylation levels of LINE-1 and Alu sequences in 48 primary nonsmall cell carcinomas and their paired adjacent tissues. We demonstrate a significant reduction of the methylation levels of both elements (p = 7.7 x 10(-14) and 9.6 x 10(-7), respectively). The methylation indices of the 2 elements correlated (p = 0.006), suggesting a possible common mechanism for their methylation maintenance. Genomic instability was measured utilizing 11 fluorescent microsatellite markers located on lung cancer hot-spot regions such as 3p, 5q 9p, 13q and 17p. Hypomethylation of both transposable elements was associated with increased genomic instability (LINE, p = 7.1 x 10(-5); Alu, p = 0.008). The reduction of the methylation index of LINE-1 and Alu following treatment of 3 lung cell lines with 5-aza-2'-deoxycitidine, consistently resulted in increased expression of both elements. Our study demonstrates the strong link between hypomethylation of transposable elements with genomic instability in non-small cell lung cancer and provides early evidence for a potential active role of these elements in lung neoplasia. As demethylating agents are now entering lung cancer trials, it is imperative to gain a greater insight into the potential reactivation of silent retrotransposons in order to advance for the clinical utilization of epigenetics in cancer therapy.

Original languageEnglish
Pages (from-to)81-7
Number of pages7
JournalInternational Journal of Cancer
Volume124
Issue number1
DOIs
Publication statusPublished - 1 Jan 2009

Keywords

  • Aged
  • Aged, 80 and over
  • Alu Elements
  • Carcinoma, Non-Small-Cell Lung/genetics
  • Cell Line, Tumor
  • DNA Methylation
  • Female
  • Genome, Human
  • Genomic Instability
  • Humans
  • Long Interspersed Nucleotide Elements/genetics
  • Lung Neoplasms/genetics
  • Male
  • Middle Aged
  • Retroelements/genetics

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