26 Chapter 1 Over recent years, several other viral and cellular biomarkers have been evaluated as a triage test for HPV-positive women, such as HPV E6 and/or E7 mRNA, HPV proteins, HPV methylation, p16INK4A/Ki-67 dual-stain cytology (CINtec® PLUS cytology test), assessment of DNA copy number alterations, analysis of miRNA expression, and host-cell DNA methylation 133. Molecular tests have the advantage over morphology-based strategies in that they comprise objective, highly reproducible techniques which are automatable and applicable to both clinician-collected cervical samples and self-collected samples. This thesis focuses on host-cell DNA methylation markers. Host-cell DNA methylation markers may offer a specific molecular approach to detect advanced CIN lesions requiring treatment and could meet the needs of cervical cancer screening in the post-vaccination era. 1.4 DNA METHYLATION-BASED BIOMARKERS FOR CERVICAL CANCER The ‘fifth base of DNA’, known as methylated cytosine, is gaining increased attention as a potential novel biomarker for cervical cancer. DNA methylation is an early and common molecular change in cervical carcinogenesis, and methylation levels increase as the disease progresses. In particular, high methylation levels have been found in cervical cancer. Nearly all cervical cancers are methylation-positive 121. DNA methylation markers have the ability to differentiate clinically relevant CIN lesions with high risk of progression to cervical cancer 122, highlighting its potential as a biomarker for screening and CIN management. Multiple studies have consistently demonstrated that DNA methylation markers have high accuracy in detection of clinically relevant cervical lesions 123-125. 1.4.1 GENOME-WIDE DISCOVERY OF HOST-CELL DNA METHYLATION MARKERS Genome-wide techniques, such as array-based methods and next generation sequencing (NGS), have enabled comprehensive studies of DNA methylation events associated with cervical cancer development 126, 127. Aberrant methylation patterns have been found in numerous genes and various host-cell DNA methylation markers have been derived thereof, including those that are further discussed in this thesis: FAM19A4 (TAFA-4, Family with sequence similarity 19 [chemokine (C-C motif)-like, member 4A]), miR124-2 (microRNA 124-2), ASCL1 (Achaete-scute family BHLH transcription factor 1), LHX8 (LIM homeobox 8) and ST6GALNAC5 (ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 5), GHSR (Growth Hormone Secretagogue receptor), SST (Somatostatin), ZIC1 (Zinc finger protein ZIC1). FAM19A4 was discovered using methylation-specific digital karyotyping of
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