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Analysis of cfDNA fragmentomics metrics and commercial targeted sequencing panels

Helzer, Kyle T. ; Sharifi, Marina N. ; Sperger, Jamie M. ; Chrostek, Matthew R. ; Bootsma, Matthew L. ; Reese, Shannon R. ; Taylor, Amy ; Kaufmann, Katie R. ; Krause, Hannah and Schehr, Jennifer , et al. (2025) In Nature Communications 16(1).
Abstract

Fragmentomics based analysis of cell-free DNA (cfDNA) has recently emerged as a method to infer epigenetic and transcriptional data. Many of these reports analyze whole genome sequencing (WGS) which is not readily available clinically. Targeted exon panels are used for clinical cfDNA variant calling. In this report, we conduct an investigation of multiple published fragmentomics methods for WGS, but on cancer exon panels. We find that strategies utilizing normalized depth metrics, as well as all exons present on the panel, generally allow for better prediction of cancer phenotypes across a range of tumor fractions, though other metrics work particularly well in specific applications. Additionally, genes from commercial clinical targeted... (More)

Fragmentomics based analysis of cell-free DNA (cfDNA) has recently emerged as a method to infer epigenetic and transcriptional data. Many of these reports analyze whole genome sequencing (WGS) which is not readily available clinically. Targeted exon panels are used for clinical cfDNA variant calling. In this report, we conduct an investigation of multiple published fragmentomics methods for WGS, but on cancer exon panels. We find that strategies utilizing normalized depth metrics, as well as all exons present on the panel, generally allow for better prediction of cancer phenotypes across a range of tumor fractions, though other metrics work particularly well in specific applications. Additionally, genes from commercial clinical targeted sequencing panels could be similarly employed for cancer phenotyping with a minimal decrease in performance despite their smaller genomic coverage. These results suggest that fragmentomics-based analysis of cfDNA can utilize targeted sequencing panels and does not necessarily require additional WGS.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
16
issue
1
article number
9122
publisher
Nature Publishing Group
external identifiers
  • scopus:105018653650
  • pmid:41087333
ISSN
2041-1723
DOI
10.1038/s41467-025-64153-z
language
English
LU publication?
yes
id
7ff3b0a4-c309-40c2-8fe7-31f82f03bae2
date added to LUP
2025-12-11 14:32:07
date last changed
2025-12-12 03:00:13
@article{7ff3b0a4-c309-40c2-8fe7-31f82f03bae2,
  abstract     = {{<p>Fragmentomics based analysis of cell-free DNA (cfDNA) has recently emerged as a method to infer epigenetic and transcriptional data. Many of these reports analyze whole genome sequencing (WGS) which is not readily available clinically. Targeted exon panels are used for clinical cfDNA variant calling. In this report, we conduct an investigation of multiple published fragmentomics methods for WGS, but on cancer exon panels. We find that strategies utilizing normalized depth metrics, as well as all exons present on the panel, generally allow for better prediction of cancer phenotypes across a range of tumor fractions, though other metrics work particularly well in specific applications. Additionally, genes from commercial clinical targeted sequencing panels could be similarly employed for cancer phenotyping with a minimal decrease in performance despite their smaller genomic coverage. These results suggest that fragmentomics-based analysis of cfDNA can utilize targeted sequencing panels and does not necessarily require additional WGS.</p>}},
  author       = {{Helzer, Kyle T. and Sharifi, Marina N. and Sperger, Jamie M. and Chrostek, Matthew R. and Bootsma, Matthew L. and Reese, Shannon R. and Taylor, Amy and Kaufmann, Katie R. and Krause, Hannah and Schehr, Jennifer and Sethakorn, Nan and Kosoff, David and Kyriakopoulos, Christos E. and Bassetti, Michael and Blitzer, Grace and Floberg, John and Sjöström, Martin and Armstrong, Andrew J. and Beltran, Himisha and McKay, Rana R. and Feng, Felix Y. and O’Regan, Ruth and Wisinski, Kari B. and Emamekhoo, Hamid and Wyatt, Alex W. and Lang, Joshua M. and Zhao, Shuang G.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Analysis of cfDNA fragmentomics metrics and commercial targeted sequencing panels}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-64153-z}},
  doi          = {{10.1038/s41467-025-64153-z}},
  volume       = {{16}},
  year         = {{2025}},
}