Aberrant DNA Methylation in Colorectal Cancer: What Should We Target?

CRCs are characterized by global DNA hypomethylation, which is associated with genomic instability and tumor initiation. CRCs also display gene-specific promoter methylation, and a subset of CRCs with elevated rates and specific patterns of methylation, termed CIMP, has been described. Some of the genes methylated in CRC are bona fide tumor-suppressor genes. However, for the majority, direct evidence of tumor-suppressor activity has not been established. Several mechanisms that underpin promoter methylation in CRC have recently been identified, including genetic variations, gain and loss of transcription factors, and response to DNA damage. DNA methyltransferase inhibitors have had limited clinical activity in CRC to date, although a number of trials are currently underway to assess their activity as immune modulators in microsatellite-stable CRC. Colorectal cancers (CRCs) are characterized by global hypomethylation and promoter-specific DNA methylation. A subset of CRCs with extensive and co-ordinate patterns of promoter methylation has also been identified, termed the CpG-island methylator phenotype. Some genes methylated in CRC are established tumor suppressors; however, for the majority, direct roles in disease initiation or progression have not been established. Herein, we examine functional evidence of specific methylated genes contributing to CRC pathogenesis, focusing on components of commonly deregulated signaling pathways. We also review current knowledge of the mechanisms underpinning promoter methylation in CRC, including genetic events, altered transcription factor binding, and DNA damage. Finally, we summarize clinical trials of DNA methyltransferase inhibitors in CRC, and propose strategies for enhancing their efficacy. Colorectal cancers (CRCs) are characterized by global hypomethylation and promoter-specific DNA methylation. A subset of CRCs with extensive and co-ordinate patterns of promoter methylation has also been identified, termed the CpG-island methylator phenotype. Some genes methylated in CRC are established tumor suppressors; however, for the majority, direct roles in disease initiation or progression have not been established. Herein, we examine functional evidence of specific methylated genes contributing to CRC pathogenesis, focusing on components of commonly deregulated signaling pathways. We also review current knowledge of the mechanisms underpinning promoter methylation in CRC, including genetic events, altered transcription factor binding, and DNA damage. Finally, we summarize clinical trials of DNA methyltransferase inhibitors in CRC, and propose strategies for enhancing their efficacy. Arthrobacter luteus restriction endonucleases (Alu) are transposable DNA sequences classified as short interspersed elements. Alu sequences are approximately 0.3 kb in length and compose approximately 10% of the human genome. monoallelic promoter methylation and transcriptional silencing of the affected allele in the majority of normal tissues in an individual. a genomic region of 500 bp or more with a C + G content greater than 55% and an observed CpG-to-expected CpG ratio of 0.65. Promoter methylation of these regions is associated with gene silencing. a covalent DNA modification induced by DNA methyltransferases whereby a methyl group (CH3) is added to a nucleotide, predominantly at the 5′ carbon of cytosine (C), to produce 5-methylcytosine (5mC). This modification most commonly occurs at CpG sites, where a cytosine is located next to a guanine. a family of enzymes that catalyse DNA methylation. There are three DNMTs expressed in mammalian cells DNMT1, DNMT3A and DNMT3B. DNMT3A and DNMT3B are de novo methyltransferases which establish methylation patterns, while DNMT1 acts to maintain methylation. a group of non-long terminal repeat (non-LTR) retrotransposons which are up to 6 kb in length, and constitute ∼15% of the human genome.