Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer.
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.
Daskalos
Alexandros
A
Roy Castle Lung Cancer Research Programme, The University of Liverpool, School of Cancer Studies, Liverpool, United Kingdom.
Nikolaidis
Georgios
G
Xinarianos
George
G
Savvari
Paraskevi
P
Cassidy
Adrian
A
Zakopoulou
Roubini
R
Kotsinas
Athanasios
A
Gorgoulis
Vassilis
V
Field
John K
JK
Liloglou
Triantafillos
T
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*
D018626:Retroelements