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Clin Epigenetics. 2015 Mar 1;7:17. doi: 10.1186/s13148-015-0051-y. eCollection 2015.

Inter-locus as well as intra-locus heterogeneity in LINE-1 promoter methylation in common human cancers suggests selective demethylation pressure at specific CpGs.

Author information

1
Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Sigmund-Freud Str. 25, 53127 Bonn, Germany.
2
Department of Urology, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.
3
Institute for Digestive Research, Lithuanian University of Health Sciences, Eiveniu g. 2, Kaunas, 50009 Lithuania.
4
Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Sigmund-Freud Str. 25, 53127 Bonn, Germany ; Bonn-Aachen International Center for IT (B-IT) Algorithmic Bioinformatics, University of Bonn, Dahlmannstr. 2, 53113 Bonn, Germany.
5
Institute of Medical Biometry, Informatics and Epidemiology (IMBIE), University of Bonn, Sigmund-Freud-Straße 25, D-53127 Bonn, Germany.
6
Bonn-Aachen International Center for IT (B-IT) Algorithmic Bioinformatics, University of Bonn, Dahlmannstr. 2, 53113 Bonn, Germany.

Abstract

BACKGROUND:

Hypomethylation of long interspersed element (LINE)-1 has been observed in tumorigenesis when using degenerate assays, which provide an average across all repeats. However, it is unknown whether individual LINE-1 loci or different CpGs within one specific LINE-1 promoter are equally affected by methylation changes. Conceivably, studying methylation changes at specific LINE-1 may be more informative than global assays for cancer diagnostics. Therefore, with the aim of mapping methylation at individual LINE-1 loci at single-CpG resolution and exploring the diagnostic potential of individual LINE-1 locus methylation, we analyzed methylation at 11 loci by pyrosequencing, next-generation bisulfite sequencing as well as global LINE-1 methylation in bladder, colon, pancreas, prostate, and stomach cancers compared to paired normal tissues and in blood samples from some of the patients compared to healthy donors.

RESULTS:

Most (72/80) tumor samples harbored significant methylation changes at at least one locus. Notably, our data revealed not only the expected hypomethylation but also hypermethylation at some loci. Specific CpGs within the LINE-1 consensus sequence appeared preferentially hypomethylated suggesting that these could act as seeds for hypomethylation. In silico analysis revealed that these CpG sites more likely faced the histones in the nucleosome. Multivariate logistic regression analysis did not reveal a significant clinical advantage of locus-specific methylation markers over global methylation markers in distinguishing tumors from normal tissues.

CONCLUSIONS:

Methylation changes at individual LINE-1 loci are heterogeneous, whereas specific CpGs within the consensus sequence appear to be more prone to hypomethylation. With a broader selection of loci, locus-specific LINE-1 methylation could become a tool for tumor detection.

KEYWORDS:

Bisulfite sequencing; Cancer; Cancer classification; DNA methylation; Global methylation; L1 loci; LINE-1; Methylation patterns; Pyrosequencing

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