Unsupervised detection of fragment length signatures of circulating tumor DNA using non-negative matrix factorization

Gabriel Renaud; Maibritt Nørgaard; Johan Lindberg; Henrik Grönberg; Bram De Laere; Jørgen Bjerggaard Jensen; Michael Borre; Claus Lindbjerg Andersen; Karina Dalsgaard Sørensen; Lasse Maretty; Søren Besenbacher

doi:10.7554/eLife.71569

Unsupervised detection of fragment length signatures of circulating tumor DNA using non-negative matrix factorization

Elife. 2022 Jul 27:11:e71569. doi: 10.7554/eLife.71569.

Authors

Gabriel Renaud^{1

2

3}, Maibritt Nørgaard^{2

3}, Johan Lindberg⁴, Henrik Grönberg⁴, Bram De Laere^{4

5

6}, Jørgen Bjerggaard Jensen⁷, Michael Borre⁸, Claus Lindbjerg Andersen^{2

3}, Karina Dalsgaard Sørensen^{2

3}, Lasse Maretty^{2

3

9}, Søren Besenbacher^{2

3

9}

Affiliations

¹ Department of Health Technology, Section of Bioinformatics, Technical University of Denmark, Kongens Lyngby, Denmark.
² Department of Molecular Medicine, Aarhus University, Aarhus, Denmark.
³ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
⁵ Cancer Research Institute Gent (CRIG), Ghent University, Ghent, Belgium.
⁶ Department of Human Structure and Repair, Ghent University, Ghent, Belgium.
⁷ Department of Urology, Regional Hospital of West Jutland, Holstebro, Denmark.
⁸ Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
⁹ Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.

Abstract

Sequencing of cell-free DNA (cfDNA) is currently being used to detect cancer by searching both for mutational and non-mutational alterations. Recent work has shown that the length distribution of cfDNA fragments from a cancer patient can inform tumor load and type. Here, we propose non-negative matrix factorization (NMF) of fragment length distributions as a novel and completely unsupervised method for studying fragment length patterns in cfDNA. Using shallow whole-genome sequencing (sWGS) of cfDNA from a cohort of patients with metastatic castration-resistant prostate cancer (mCRPC), we demonstrate how NMF accurately infers the true tumor fragment length distribution as an NMF component - and that the sample weights of this component correlate with ctDNA levels (r=0.75). We further demonstrate how using several NMF components enables accurate cancer detection on data from various early stage cancers (AUC = 0.96). Finally, we show that NMF, when applied across genomic regions, can be used to discover fragment length signatures associated with open chromatin.

Keywords: cancer biology; cancer genomics; cell-free DNA; genetics; genomics; human; liquid biopsy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics
Cell-Free Nucleic Acids*
Circulating Tumor DNA* / genetics
Genomics / methods
Humans
Male
Mutation

Substances

Biomarkers, Tumor
Cell-Free Nucleic Acids
Circulating Tumor DNA

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.