Universität zu Köln

Hudecova, Irena ORCID: 0000-0003-3823-9896, Smith, Christopher G., Hansel-Hertsch, Robert, Chilamakuri, Chandra S., Morris, James A., Vijayaraghavan, Aadhitthya, Heider, Katrin ORCID: 0000-0003-4035-1668, Chandrananda, Dineika ORCID: 0000-0002-8834-9500, Cooper, Wendy N., Gale, Davina, Garcia-Corbacho, Javier, Pacey, Simon, Baird, Richard D., Rosenfeld, Nitzan and Mouliere, Florent ORCID: 0000-0001-7043-0514 (2022). Characteristics, origin, and potential for cancer diagnostics of ultrashort plasma cell-free DNA. Genome Res., 32 (2). S. 215 - 228. COLD SPRING HARBOR: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. ISSN 1549-5469

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Abstract

Current evidence suggests that plasma cell-free DNA (cfDNA) is fragmented around a mode of 166 bp. Data supporting this view has been mainly acquired through the analysis of double-stranded cfDNA. The characteristics and diagnostic potential of single-stranded and damaged double-stranded cfDNA in healthy individuals and cancer patients remain unclear. Here, through a combination of high-affinity magnetic bead-based DNA extraction and single-stranded DNA sequencing library preparation (MB-ssDNA), we report the discovery of a large proportion of cfDNA fragments centered at similar to 50 bp. We show that these ultrashort cfDNA fragments have a greater relative abundance in plasma of healthy individuals (median = 19.1% of all sequenced cfDNA fragments, n = 28) than in plasma of patients with cancer (median = 14.2%, n = 21, P < 0.0001). The ultrashort cfDNA fragments map to accessible chromatin regions of blood cells, particularly in promoter regions with the potential to adopt G-quadruplex (G4) DNA secondary structures. G4-positive promoter chromatin accessibility is significantly enriched in ultrashort plasma cfDNA fragments from healthy individuals relative to patients with cancers (P < 0.0001), in whom G4-cfDNA enrichment is inversely associated with copy number aberration-inferred tumor fractions. Our findings redraw the landscape of cfDNA fragmentation by identifying and characterizing a novel population of ultrashort plasma cfDNA fragments. Sequencing of MB-ssDNA libraries could facilitate the characterization of gene regulatory regions and DNA secondary structures via liquid biopsy. Our data underline the diagnostic potential of ultrashort cfDNA through classification for cancer patients.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hudecova, Irena UNSPECIFIED orcid.org/0000-0003-3823-9896 UNSPECIFIED Smith, Christopher G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansel-Hertsch, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Chilamakuri, Chandra S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Morris, James A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vijayaraghavan, Aadhitthya UNSPECIFIED UNSPECIFIED UNSPECIFIED Heider, Katrin UNSPECIFIED orcid.org/0000-0003-4035-1668 UNSPECIFIED Chandrananda, Dineika UNSPECIFIED orcid.org/0000-0002-8834-9500 UNSPECIFIED Cooper, Wendy N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gale, Davina UNSPECIFIED UNSPECIFIED UNSPECIFIED Garcia-Corbacho, Javier UNSPECIFIED UNSPECIFIED UNSPECIFIED Pacey, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Baird, Richard D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenfeld, Nitzan UNSPECIFIED UNSPECIFIED UNSPECIFIED Mouliere, Florent UNSPECIFIED orcid.org/0000-0001-7043-0514 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-690824
DOI:	10.1101/gr.275691.121
Journal or Publication Title:	Genome Res.
Volume:	32
Number:	2
Page Range:	S. 215 - 228
Date:	2022
Publisher:	COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
Place of Publication:	COLD SPRING HARBOR
ISSN:	1549-5469
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language G-QUADRUPLEX STRUCTURES; LIBRARY PREPARATION; HUMAN GENOME; QUANTITY; QUALITY; MARKER; ROLES; SERUM; LONG Multiple languages Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69082