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The mutational signatures of formalin fixation on the human genome

Author

Listed:
  • Qingli Guo

    (University of Helsinki
    Queen Mary University of London)

  • Eszter Lakatos

    (Queen Mary University of London
    Institute of Cancer Research)

  • Ibrahim Al Bakir

    (Queen Mary University of London)

  • Kit Curtius

    (Queen Mary University of London
    University of California San Diego)

  • Trevor A. Graham

    (Queen Mary University of London
    Institute of Cancer Research)

  • Ville Mustonen

    (University of Helsinki
    University of Helsinki)

Abstract

Clinical archives of patient material near-exclusively consist of formalin-fixed and paraffin-embedded (FFPE) blocks. The ability to precisely characterise mutational signatures from FFPE-derived DNA has tremendous translational potential. However, sequencing of DNA derived from FFPE material is known to be riddled with artefacts. Here we derive genome-wide mutational signatures caused by formalin fixation. We show that the FFPE-signature is highly similar to signature 30 (the signature of Base Excision Repair deficiency due to NTHL1 mutations), and chemical repair of DNA lesions leads to a signature highly similar to signature 1 (clock-like signature due to spontaneous deamination of methylcytosine). We demonstrate that using uncorrected mutational catalogues of FFPE samples leads to major mis-assignment of signature activities. To correct for this, we introduce FFPEsig, a computational algorithm to rectify the formalin-induced artefacts in the mutational catalogue. We demonstrate that FFPEsig enables accurate mutational signature analysis both in simulated and whole-genome sequenced FFPE cancer samples. FFPEsig thus provides an opportunity to unlock additional clinical potential of archival patient tissues.

Suggested Citation

  • Qingli Guo & Eszter Lakatos & Ibrahim Al Bakir & Kit Curtius & Trevor A. Graham & Ville Mustonen, 2022. "The mutational signatures of formalin fixation on the human genome," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32041-5
    DOI: 10.1038/s41467-022-32041-5
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    References listed on IDEAS

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