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Discovering fragment length signatures of circulating tumor DNA using Non-negative Matrix Factorization

Renaud, G.; Noergaard, M.; Lindberg, J.; Groenberg, H.; De Laere, B.; Jensen, J. B.; Borre, M.; Andersen, C. L.; Soerensen, K. D.; Maretty, L.; Besenbacher, S.

2021-06-10 bioinformatics
10.1101/2021.06.09.447533 bioRxiv
Show 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 method to study fragment lengths in cfDNA samples. 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.

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