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Title
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Enhancing cancer detection through novel DNA methylation strategies and biomarkers = Het verbeteren van kankerdetectie via nieuwe DNA methylatie strategieën en biomerkers
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Author
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Abstract
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| Cancer remains a global health challenge despite advancements in biomedical research. Early-stage cancers are treatable, but therapy becomes difficult in later stages, underscoring the importance of timely screening. Traditional diagnostics like imaging and tissue biopsies are invasive and not always precise, necessitating the search for reliable biomarkers and sensitive technologies. In this view, DNA methylation has emerged as a promising biomarker for early cancer detection. In the first part of this thesis, we have investigated novel biomarkers for colorectal cancer (CRC). First, we analysed 500 stage IV CRCs to identify factors associated with interval cancer (IC) stage IV CRC that remained undetected by the fecal immunochemical test (FIT). Findings showed a higher likelihood of neuroendocrine tumors (NETs) and lymphovascular invasion in FIT-IC CRCs, and importantly, tumor location significantly influenced these associations. Secondly, we evaluated DNA methylation patterns in colorectal tissues, identifying 13 differentially methylated sites. Our final model achieved a sensitivity of 96% and specificity of 95% in distinguishing adenomas from carcinomas. The second part delves into epigenomics for multi-cancer detection. First, a multiplex droplet digital PCR (ddPCR) assay was developed using differentially methylated targets from The Cancer Genome Atlas (TCGA). This assay demonstrated high accuracy but was limited in target numbers for simultaneous analysis. To overcome this, the IMPRESS (Improved Methylation Profiling using Restriction Enzymes and smMIP Sequencing) technique was developed, facilitating multiplex analysis without bisulfite conversion. IMPRESS achieved high sensitivity (95%) and specificity (91%) in distinguishing tumor from normal tissue across eight cancer types. The final part focuses on assays for CRC and breast cancer (BRCA) using IMPRESS. Differentially methylated sites were identified from public datasets, and a two-step assay (a cancer detection panel and an invasiveness detection panel) was created for both cancers. For CRC, the cancer detection panel achieved 100% sensitivity and specificity, while the invasiveness detection panel showed 80% sensitivity and 92% specificity. For BRCA, the cancer detection panel had 94.4% sensitivity and 100% specificity, with the invasiveness detection panel achieving 66.7% sensitivity and 88.9% specificity. These results indicate high sensitivity and specificity for distinguishing cancerous from normal samples, with good accuracy for differentiating precancerous from invasive tumors. Further research is needed to validate these panels in plasma-derived liquid biopsies. The integration of advanced technologies like multiplex ddPCR and IMPRESS highlights the importance of epigenetic research in cancer diagnostics, and this thesis paves the way for improved clinical applications in cancer screening and detection. |
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Language
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English
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Publication
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Antwerpen
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Universiteit Antwerpen, Faculteit Farmaceutische, Biomedische en Diergeneeskundige Wetenschappen, Departement Biomedische Wetenschappen
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2024
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DOI
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10.63028/10067/2078550151162165141
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Volume/pages
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283 p.
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Note
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op de Beeck, Ken [Supervisor]
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Van Camp, Guy [Supervisor]
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Peeters, Marc [Supervisor]
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Full text (open access)
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