Changes in correlation between promoter methylation and gene expression in cancer

BMC Genomics

Research Article

Valentina Boeva¹  Matahi Moarii¹  Jean-Philippe Vert¹  Fabien Reyal² 

[1] CBIO-Centre for Computational Biology, Mines Paristech, PSL-Research University, 35 Rue Saint-Honore, F-77300, Fontainebleau, France;Department of Bioinformatics, Biostatistics and System Biology, Institut Curie, 11-13 Rue Pierre et Marie Curie, F-75248, Paris, France;U900, INSERM, 11-13 Rue Pierre et Marie Curie, F-75248, Paris, France;UMR932, Immunity and Cancer Team, Institut Curie, 26 Rue d’Ulm, 75006, Paris, France;Department of Translational Research, Residual Tumor and Response to Treatment Team, Institut Curie, 26 Rue d’Ulm, 75006, Paris, France;Department of Surgery, Institut Curie, 26 Rue d’Ulm, 75006, Paris, France;

关键词: Epigenetic regulation;    Cancer;    CpG Island methylator phenotype;   

DOI  :  10.1186/s12864-015-1994-2

 received in 2015-05-11, accepted in 2015-10-06,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMethylation of high-density CpG regions known as CpG Islands (CGIs) has been widely described as a mechanism associated with gene expression regulation. Aberrant promoter methylation is considered a hallmark of cancer involved in silencing of tumor suppressor genes and activation of oncogenes. However, recent studies have also challenged the simple model of gene expression control by promoter methylation in cancer, and the precise mechanism of and role played by changes in DNA methylation in carcinogenesis remains elusive.ResultsUsing a large dataset of 672 matched cancerous and healthy methylomes, gene expression, and copy number profiles accross 3 types of tissues from The Cancer Genome Atlas (TCGA), we perform a detailed meta-analysis to clarify the interplay between promoter methylation and gene expression in normal and cancer samples. On the one hand, we recover the existence of a CpG island methylator phenotype (CIMP) with prognostic value in a subset of breast, colon and lung cancer samples, where a common subset of promoter CGIs hypomethylated in normal samples become hypermethylated. However, this hypermethylation is not accompanied by a decrease in expression of the corresponding genes, which are already lowly expressed in the normal genes. On the other hand, we identify tissue-specific sets of genes, different between normal and cancer samples, whose inter-individual variation in expression is significantly correlated with the variation in methylation of the 3’ flanking regions of the promoter CGIs. These subsets of genes are not the same in the different tissues, nor between normal and cancerous samples, but transcription factors are over-represented in all subsets.ConclusionOur results suggest that epigenetic reprogramming in cancer does not contribute to cancer development via direct inhibition of gene expression through promoter hypermethylation. It may instead modify how the expression of a few specific genes, particularly transcription factors, are associated with DNA methylation variations in a tissue-dependent manner.

【 授权许可】

CC BY   
© Moarii et al. 2015

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