Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue
Background and aims
Malignant cells often exhibit perturbations in the pattern of cytosine methylation. Hypermethylation of CpG islands has been extensively documented, but genome-wide hypomethylation is also a common feature of malignant cells. The bulk of cytosine methylation in the mammalian genome occurs on repetitive elements. This study analysed the methylation status of L1 retrotransposons in colorectal cancer.
Patients and methods
Methylation-sensitive Southern blotting was used to determine L1 promoter methylation in colon tumours, adjacent normal tissue, and normal colonic mucosa from healthy individuals.
Hypomethylation of L1 promoter sequences was detected in all tumours but was also detected in the histologically normal colonic mucosa of 6 of 19 cancer patients, even at a considerable distance from the tumour. L1 hypomethylation was not detected in matched normal peripheral blood, lymph node or smooth muscle tissue from cancer patients or in the colonic mucosa of 14 healthy individuals. We also assayed for the total proportion of methylated CpG in normal bowel specimens from normal and colon cancer patients. Normal mucosa from cancer patients exhibited lower levels of genomic methylation than the mucosa from healthy individuals, and levels were significantly lower in those patients exhibiting L1 promoter hypomethylation.
These results suggest that genomic hypomethylation is an early event in tumourigenesis. Progressive demethylation of L1 promoter sequences could lead to disturbance of normal gene expression and facilitate the process of neoplastic progression.
KeywordsEpigenetic Retroelement Cytosine methylation Transcriptional interference
- 13.Roman-Gomez J, Castillejo JA, Jimenez A, Gonzalez MG, Moreno F, Rodriguez Mdel C, Barrios M, Maldonado J, Torres A (2002) 5’ CpG island hypermethylation is associated with transcriptional silencing of the p21 (CIP1/WAF1/SDI1) gene and confers poor prognosis in acute lymphoblastic leukemia. Blood 99:2291–2296CrossRefPubMedGoogle Scholar
- 20.Crowther PJ, Doherty JP, Linsenmeyer ME, Williamson MR, Woodcock DM (1991) Revised genomic consensus for the hypermethylated CpG island region of the human L1 transposon and integration sites of full length L1 elements from recombinant clones made using methylation-tolerant host strains. Nucleic Acids Res 19:2395–2401PubMedGoogle Scholar
- 26.McClintock B (1968) The states of a gene locus in maize. Carnegie Institute of Washington Yearbook 66:20–28Google Scholar
- 29.Kashkush K, Feldman M, Levy AA (2002) Transcriptional activation of retrotransposons alters the expression of adjacent genes in wheat. Nat Genet 16:16Google Scholar