The mutational signatures of formalin fixation on the human genome

Qingli Guo, Eszter Lakatos, Ibrahim Al Bakir, Kit Curtius, Trevor A. Graham () and Ville Mustonen ()
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Qingli Guo: University of Helsinki
Eszter Lakatos: Queen Mary University of London
Ibrahim Al Bakir: Queen Mary University of London
Kit Curtius: Queen Mary University of London
Trevor A. Graham: Queen Mary University of London
Ville Mustonen: University of Helsinki

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32041-5

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