12 Chapter 1 Cancer cells exhibit abnormal methylation patterns, which can drive malignant transformation. Global hypomethylation along the genome contributes to genomic instability (16), while focal hypermethylation is associated with gene promoters and leads to the silencing of genes involved in tumor suppression (15). DNA methylation changes are already observed during the most early phases of carcinogenesis and are therefore attractive for early cancer detection (15, 16). It has been shown that DNA methylation markers even allow the detection of precancerous lesions of the anus (21), cervix (22), colon (23), oral cavity (24), and vulva (25). The work described in this thesis focuses on promoter hypermethylation of cancerrelated genes as biomarkers for cancer detection (Figure 1). DNA methylation involves a chemical reaction in which a methyl group (CH3) is attached to the cytosine base of the DNA. This covalent transfer is mediated by the DNA methyltransferase (DNMT) enzyme family and produces 5-methylcytosine. Methylation of the cytosine base occurs exclusively in CG-rich regions, also referred to as CpG islands. CpG islands are found in the promoter regions of many genes, including those associated with tumor suppression, referred to as tumor suppressor genes (26). Me Me Me Inactive Me Methylated CpG Unmethylated CpG Active NH2 N N O cytosine N NH2 CH3 N O 5-methylcytosine DNMT Hypermethylation at gene promoters Loss of tumor suppressor gene function Figure 1: Gene inactivation by DNA methylation. Gene expression can be silenced by hypermethylation of the promoter region, rendering tumor suppressor genes inactive. During DNA methylation, a methyl group (CH3) is added to the cytosine base by DNA methyltransferases (DNMTs) at CG-rich regions, known as CpG islands. Created with BioRender.com.
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