Changes in correlation between promoter methylation and gene expression in cancer

Area of Science:

• Genomics
• Epigenetics
• Cancer Biology

Background:

• CpG Island (CGI) methylation regulates gene expression.
• Aberrant promoter methylation is a cancer hallmark, silencing tumor suppressors and activating oncogenes.
• The precise role of DNA methylation changes in carcinogenesis is still unclear.

Purpose of the Study:

• To analyze the interplay between promoter methylation and gene expression in normal and cancer tissues.
• To investigate the role of DNA methylation in cancer development.
• To clarify the mechanism of gene expression control by DNA methylation in cancer.

Main Methods:

• Meta-analysis of 672 matched cancerous and healthy methylomes, gene expression, and copy number profiles from The Cancer Genome Atlas (TCGA).
• Analysis of CpG island methylation status and gene expression in breast, colon, and lung cancer samples.
• Identification of tissue-specific gene sets correlated with methylation variations in promoter CGI flanking regions.

Main Results:

• A CpG island methylator phenotype (CIMP) with prognostic value was identified in a subset of cancers.
• Hypermethylation of promoter CGIs in cancer was not associated with decreased gene expression.
• Tissue-specific gene sets, enriched for transcription factors, showed correlations between gene expression and 3' flanking CGI methylation variations.

Conclusions:

• Epigenetic reprogramming in cancer may not directly inhibit gene expression via promoter hypermethylation.
• DNA methylation variations may modulate the expression of specific genes, especially transcription factors, in a tissue-dependent manner.
• The findings challenge the simple model of gene expression control by promoter methylation in cancer.