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Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor

Islam, SMA; Díaz-Gay, M; Wu, Y; Barnes, M; Vangara, R; Bergstrom, EN; He, Y; ... Alexandrov, LB; + view all (2022) Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. Cell Genomics , 2 (11) , Article 100179. 10.1016/j.xgen.2022.100179. Green open access

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Abstract

Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues.

Type: Article
Title: Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.xgen.2022.100179
Publisher version: https://doi.org/10.1016/j.xgen.2022.100179
Language: English
Additional information: © 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: cancer genomics, genomics, mutagenesis, mutational signatures
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
URI: https://discovery.ucl.ac.uk/id/eprint/10160247
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