Breast Cancer Patients: Diagnostic Epigenetic Markers in Blood

Abstract

Epigenetic changes are defined as changes of gene expression without changes in the DNA sequence. Both DNA methylation and histone modifications are essential in normal mammalian development. Recently, it has been shown that epigenetic alterations play an important role in tumorigenesis and represent alternative means of activation of tumor oncogenes, inactivation of tumor suppressor genes, and induction of genomic instability (Jones and Baylin, 2007). During the last 2 decades, much effort has been focused on the role of DNA methylation changes in cancer development and their utilities in cancer detection. It is now clear that histone modifications are an integral part of the epigenetic programming. DNA methylation, referring here to the addition of a methyl group to the cytosine in the cytosine-phosphate-guanine (CpG) dinucleotides, plays an important role in normal development, genomic stability, and regulation of gene expression. In normal cells, the majority of CpG dinucleotides is located in the repetitive sequences of the genome and methylated. Approximately, 50% of housekeeping genes contains a CpG rich region (called the CpG island) in their promoter region, which is not methylated regardless of whether the gene is transcribed or not. On the contrary, tumor cells are characterized by both global hypomethylation and gene-specific hypermethylation (Jones and Baylin, 2007). Hypomethylation of repetitive sequences leads to genome instability, while promoter hypermethylation leads to transcriptional silencing of many tumor suppressor genes, with similar consequence as genetic mutations. Histone modifications, referring to acetylation, methylation, phosphorylation, ubiquitination, and sumoylation of amino acids in histone tails, collectively form histone codes that link various chromatin structures to gene expression states. Accumulating evidence suggests that acetylation and methylation of different lysine and arginine residues in histones H3 and H4 are associated with either transcriptionally active or transcriptionally repressed states of gene expression. For example, acetylated histones are associated with transcribed genes, while deacetylated histones are associated with silenced genes. Methylated lysine 9 (K9) or K27 on H3 and K20 on H4 are generally associated with transcription repressed genes, whereas methylated K4, K36, and K79 are found mainly in active chromatin (Kouzarides, 11 Breast Cancer Patients: Diagnostic Epigenetic Markers in Blood