Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Ulz, P.
Epigenetic traces in cell-free DNA
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin, [ Dissertation ] Graz Medical University; 2019. pp. 97
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Höfler Gerald
- Schimek Michael
- Speicher Michael
- Altmetrics:
- Abstract:
- Alterations in epigenetic regulatory regions in the genome are important drivers of tumorigenesis, but non-invasive assays for assessing them are lacking. In this work, the feasibility of inferring altered epigenetic regulatory mechanism in solid tumors from their nucleosome footprint in circulating cell-free DNA was evaluated. Since cell-free DNA fragments are associated to histone proteins, changes in nucleosome synchronization should lead to non-random coverage in whole-genome sequencing data. In a set of late-stage cancer samples, patient-specific as well as tumor-specific patterns can be observed using this method. Especially altered nucleosome positioning due to transcription factor binding showed great potential in uncovering biological mechanism of the primary tumor by non- invasive means. Specifically, inferred binding patterns for the transcription factors AR, HOXB13, and NKX3-1 allowed classification of patients by tumor type, including sub- types of prostate cancer, which has clinical implications for the management of patients. Moreover, novel transcription factors that play a role in the carcinogenesis of colorectal cancer were identified. Lastly, transcription factor accessibilities were used to construct a cancer classification algorithm that can reliably detect colon carcinoma samples even at early stages. Moreover, several other epigenetic regulatory mechanism leave a trace in cfDNA fragmentation patterns, however, the respective signal strengths are lower and nucleosome synchronization is more difficult to assess. This approach for mapping tumor- specific alteration of epigenetic regulatory mechanisms in vivo based on blood samples makes a key part of the noncoding genome amenable for clinical analysis.