title: Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer.
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.
authors.affiliation: Roy Castle Lung Cancer Research Programme, The University of Liverpool, School of Cancer Studies, Liverpool, United Kingdom.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Daskalos
authors.forename: Georgios
authors.initials: G
authors.lastname: Nikolaidis
authors.forename: George
authors.initials: G
authors.lastname: Xinarianos
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Savvari
authors.forename: Adrian
authors.initials: A
authors.lastname: Cassidy
authors.forename: Roubini
authors.initials: R
authors.lastname: Zakopoulou
authors.forename: Athanasios
authors.initials: A
authors.lastname: Kotsinas
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Triantafillos
authors.initials: T
authors.lastname: Liloglou
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020087:Alu Elements; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018626:Retroelements / Q000235:genetics*
chemical_list: D018626:Retroelements