11 General introduction Reliable cancer detection requires highly sensitive and specific methods. A measurable characteristic that objectively reflects the presence of a certain biological condition is known as a biological marker, or shortly: a biomarker (11). The perfect biomarker would have 100% sensitivity and 100% specificity, meaning that individuals with disease will always get a positive test result and individuals without disease will always score negative. Combining patient-friendly sampling methods with reliable biomarker testing can serve as a powerful tool that is convenient for patients and effective in detecting cancer at a curable stage. Finding a suitable biomarker for early cancer diagnosis is challenging. No one-sizefits-all approach exists, as cancer is a complex heterogeneous disease in which each cancer type carries a unique molecular background. Even cancers that originate from the same organ or tissue type may differ extensively in their genetic profile. The complexity of cancer development and its underlying mechanisms are detailed within the conceptual hallmarks of cancer framework, as primarily described by Hanahan and Weinberg (12). The original model described six general mechanisms that drive cancer development, including self-sufficiency in growth signals, insensitivity to growthinhibitory signals, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. During the last two decades, the original model has been updated twice (13, 14), which accentuates the continued advances in understanding the cellular and genetic mechanisms involved in carcinogenesis. The most recent update of the hallmarks of cancer includes the crucial role of non-mutational epigenetic reprogramming in malignant transformation (14). Epigenetics refers to the reprogramming of cells by altering the expression of genes, without modifying the DNA sequence itself. This adds an additional layer of complexity to the genome. One of the well-studied epigenetic mechanisms is DNA methylation (15). This epigenetic alteration is associated with gene silencing and poses an attractive biomarker to detect cancer early (16). 1.2 DNA methylation as biomarker for cancer detection The DNA methylation machinery is a crucial regulator of gene expression and essential for normal tissue development and homeostasis. The reversible nature of DNA methylation allows dynamic changes during embryonic development and the generation of tissue-specific methylation marks (17). Examples of fundamental processes in which DNA methylation is involved include the repression of repetitive elements, inactivation of one copy of the X-chromosome in females, and the silencing of gene transcription (17, 18). Exposure to chemical compounds (e.g. tobacco smoke) or normal physiological processes (e.g. aging) can also alter DNA methylation levels (19, 20). 1
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