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

Clinical Epigenetics

Osman El-Maarri¹  Wolfgang A Schulz²  Antanas Gulbinas³  Johannes Oldenburg¹  Holger Fröhlich⁴  Rolf Fimmers⁵  Heike Singer¹  Amit Sharma¹  Ioanna Dimitriou⁵  Muhammad Ahmer Jamil⁴  Arijit Biswas¹  Albertas Dauksa³  Wolfgang Goering²  Nicole Nüsgen¹ 

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

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

Others  :  1147917
DOI  :  10.1186/s13148-015-0051-y

 received in 2014-10-14, accepted in 2015-02-02,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Nüsgen et al.; licensee BioMed Central.

【 图 表 】

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