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

TY - JOUR

T1 - Unsupervised detection of fragment length signatures of circulating tumor DNA using non-negative matrix factorization

AU - Renaud, Gabriel

AU - Nørgaard, Maibritt

AU - Lindberg, Johan

AU - Grönberg, Henrik

AU - De Laere, Bram

AU - Jensen, Jørgen Bjerggaard

AU - Borre, Michael

AU - Andersen, Claus Lindbjerg

AU - Sørensen, Karina Dalsgaard

AU - Maretty, Lasse

AU - Besenbacher, Søren

N1 - © 2022, Renaud et al.

PY - 2022/7

Y1 - 2022/7

N2 - 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.

AB - 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.

KW - Biomarkers, Tumor/genetics

KW - Cell-Free Nucleic Acids

KW - Circulating Tumor DNA/genetics

KW - Genomics/methods

KW - Humans

KW - Male

KW - Mutation

U2 - 10.7554/ELIFE.71569

DO - 10.7554/ELIFE.71569

M3 - Journal article

C2 - 35894300

SN - 2050-084X

VL - 11

JO - eLife

JF - eLife

M1 - e71569

ER -