Unsupervised detection of fragment length signatures of circulating tumor DNA using non-negative matrix factorization.
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ABSTRACT:
SUBMITTER: Renaud G
PROVIDER: S-EPMC9363120 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
Publications
Unsupervised detection of fragment length signatures of circulating tumor DNA using non-negative matrix factorization.
Renaud Gabriel G Nørgaard Maibritt M Lindberg Johan J Grönberg Henrik H De Laere Bram B Jensen Jørgen Bjerggaard JB Borre Michael M Andersen Claus Lindbjerg CL Sørensen Karina Dalsgaard KD Maretty Lasse L Besenbacher Søren S
eLife 20220727
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 cf ...[more]
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| S-EPMC6559648 | biostudies-literature
Project description:BackgroundLate detection of hepatocellular carcinoma (HCC) results in an overall 5-year survival rate of less than 16%. Liquid biopsy (LB) assays based on detecting circulating tumor DNA (ctDNA) might provide an opportunity to detect HCC early noninvasively. Increasing evidence indicates that ctDNA detection using mutation-based assays is significantly challenged by the abundance of white blood cell-derived mutations, non-tumor tissue-derived somatic mutations in plasma, and the mutational tumor heterogeneity.MethodsHere, we employed concurrent analysis of cancer-related mutations, and their fragment length profiles to differentiate mutations from different sources. To distinguish persons with HCC (PwHCC) from healthy participants, we built a classification model using three fragmentomic features of ctDNA through deep sequencing of thirteen genes associated with HCC.ResultsOur model achieved an area under the curve (AUC) of 0.88, a sensitivity of 89%, and a specificity of 82% in the discovery cohort consisting of 55 PwHCC and 55 healthy participants. In an independent validation cohort of 54 PwHCC and 53 healthy participants, the established model achieved comparable classification performance with an AUC of 0.86 and yielded a sensitivity and specificity of 81%.ConclusionsOur study provides a rationale for subsequent clinical evaluation of our assay performance in a large-scale prospective study.
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Project description:MotivationUnderstanding the underlying mutational processes of cancer patients has been a long-standing goal in the community and promises to provide new insights that could improve cancer diagnoses and treatments. Mutational signatures are summaries of the mutational processes, and improving the derivation of mutational signatures can yield new discoveries previously obscured by technical and biological confounders. Results from existing mutational signature extraction methods depend on the size of available patient cohort and solely focus on the analysis of mutation count data without considering the exploitation of metadata.ResultsHere we present a supervised method that utilizes cancer type as metadata to extract more distinctive signatures. More specifically, we use a negative binomial non-negative matrix factorization and add a support vector machine loss. We show that mutational signatures extracted by our proposed method have a lower reconstruction error and are designed to be more predictive of cancer type than those generated by unsupervised methods. This design reduces the need for elaborate post-processing strategies in order to recover most of the known signatures unlike the existing unsupervised signature extraction methods. Signatures extracted by a supervised model used in conjunction with cancer-type labels are also more robust, especially when using small and potentially cancer-type limited patient cohorts. Finally, we adapted our model such that molecular features can be utilized to derive an according mutational signature. We used APOBEC expression and MUTYH mutation status to demonstrate the possibilities that arise from this ability. We conclude that our method, which exploits available metadata, improves the quality of mutational signatures as well as helps derive more interpretable representations.Availability and implementationhttps://github.com/ratschlab/SNBNMF-mutsig-public.Supplementary informationSupplementary data are available at Bioinformatics online.
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