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The mutational signatures of formalin fixation on the human genome

View ORCID ProfileQingli Guo, Eszter Lakatos, Ibrahim Al Bakir, View ORCID ProfileKit Curtius, View ORCID ProfileTrevor A. Graham, View ORCID ProfileVille Mustonen
doi: https://doi.org/10.1101/2021.03.11.434918
Qingli Guo
1Organismal and Evolutionary Biology Research Programme, Department of Computer Science, University of Helsinki, 00014 Helsinki, Finland
2Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Sq, London, EC1M 6BQ, UK
3Institute of Biotechnology, Helsinki Institute for Information Technology, University of Helsinki, 00014 Helsinki, Finland
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  • ORCID record for Qingli Guo
Eszter Lakatos
2Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Sq, London, EC1M 6BQ, UK
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Ibrahim Al Bakir
2Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Sq, London, EC1M 6BQ, UK
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Kit Curtius
2Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Sq, London, EC1M 6BQ, UK
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Trevor A. Graham
2Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Sq, London, EC1M 6BQ, UK
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  • For correspondence: t.graham@qmul.ac.uk v.mustonen@helsinki.fi
Ville Mustonen
1Organismal and Evolutionary Biology Research Programme, Department of Computer Science, University of Helsinki, 00014 Helsinki, Finland
3Institute of Biotechnology, Helsinki Institute for Information Technology, University of Helsinki, 00014 Helsinki, Finland
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  • For correspondence: t.graham@qmul.ac.uk v.mustonen@helsinki.fi
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Abstract

Background Formalin fixation and paraffin embedding (FFPE) of patient material remains standard practice in clinical pathology labs around the world. Clinical archives of patient material near-exclusively consist of FFPE blocks. The ability to perform high quality genome sequencing on FFPE-derived DNA would accelerate a broad spectrum of medical research. However, formalin is a recognised mutagen and sequencing of DNA derived from FFPE material is known to be riddled with artefactual mutations.

Results Here we derive genome-wide mutational signatures caused by formalin fixation, and provide a computational method to correct mutational profiles for these formalin-induced artefacts. We show that the FFPE-signature is dominated by C>T transitions caused by cytosine deamination, and has very high similarity to COSMIC signature SBS30 (base excision repair deficiency due to inactivation mutations in NTHL1). Further, we demonstrate that chemical repair of formalin-induced DNA lesions, a process that is routinely performed as part of sequencing library preparation, leads to a signature highly similar to COSMIC signature SBS1 (spontaneous deamination of methylated cytosine). Next, we design FFPEsig, a computational method to remove the formalin-induced artefacts from mutational counts. We prove the efficacy of this method by generating synthetic FFPE samples using 2,780 cancer genomes from the Pan-Cancer Analysis of Whole Genome (PCAWG) project, and via analysis of FFPE-derived genome sequencing data from colorectal cancers.

Conclusions Formalin fixation leaves a predictable mutational footprint across the genome. The application of our FFPEsig software corrects the mutational profile for the influence of formalin, enabling robust mutational signature analysis in FFPE-derived patient material.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Contact information of the authors qingli.guo{at}helsinki.fi, e.lakatos{at}qmul.ac.uk, i.albakir{at}qmul.ac.uk, k.curtius{at}qmul.ac.uk, t.graham{at}qmul.ac.uk, v.mustonen{at}helsinki.fi

  • https://github.com/QingliGuo/FFPEsig

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 12, 2021.
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The mutational signatures of formalin fixation on the human genome
Qingli Guo, Eszter Lakatos, Ibrahim Al Bakir, Kit Curtius, Trevor A. Graham, Ville Mustonen
bioRxiv 2021.03.11.434918; doi: https://doi.org/10.1101/2021.03.11.434918
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The mutational signatures of formalin fixation on the human genome
Qingli Guo, Eszter Lakatos, Ibrahim Al Bakir, Kit Curtius, Trevor A. Graham, Ville Mustonen
bioRxiv 2021.03.11.434918; doi: https://doi.org/10.1101/2021.03.11.434918

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