Changes in correlation between promoter methylation and gene expression in cancer.
BACKGROUND
Methylation 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.


RESULTS
Using 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.


CONCLUSIONS
Our 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.
CBIO-Centre for Computational Biology, Mines Paristech, PSL-Research University, 35 Rue Saint-Honore, Fontainebleau, F-77300, France. matahi.moarii@mines-paristech.fr.|Department of Bioinformatics, Biostatistics and System Biology, Institut Curie, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France. matahi.moarii@mines-paristech.fr.|U900, INSERM, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France. matahi.moarii@mines-paristech.fr.
Matahi
M
Moarii
CBIO-Centre for Computational Biology, Mines Paristech, PSL-Research University, 35 Rue Saint-Honore, Fontainebleau, F-77300, France. valentina.boeva@curie.fr.|Department of Bioinformatics, Biostatistics and System Biology, Institut Curie, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France. valentina.boeva@curie.fr.|U900, INSERM, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France. valentina.boeva@curie.fr.
Valentina
V
Boeva
CBIO-Centre for Computational Biology, Mines Paristech, PSL-Research University, 35 Rue Saint-Honore, Fontainebleau, F-77300, France. jean-philippe.vert@mines-paristech.fr.|Department of Bioinformatics, Biostatistics and System Biology, Institut Curie, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France. jean-philippe.vert@mines-paristech.fr.|U900, INSERM, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France. jean-philippe.vert@mines-paristech.fr.
Jean-Philippe
JP
Vert
UMR932, Immunity and Cancer Team, Institut Curie, 26 Rue d'Ulm, Paris, 75006, France. fabien.reyal@curie.fr.|Department of Translational Research, Residual Tumor and Response to Treatment Team, Institut Curie, 26 Rue d'Ulm, Paris, 75006, France. fabien.reyal@curie.fr.|Department of Surgery, Institut Curie, 26 Rue d'Ulm, Paris, 75006, France. fabien.reyal@curie.fr.
Fabien
F
Reyal
D019175:DNA Methylation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*