4.8 Article

The mutational signatures of formalin fixation on the human genome

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32041-5

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  1. Cancer Research UK [A19771, A16581]
  2. Barts Charity [472-2300]
  3. Academy of Finland [345829]
  4. Helsinki University Library
  5. QMUL Research-IT

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Clinical archives of patient material are predominantly composed of FFPE blocks. However, sequencing DNA derived from FFPE material is known to have artifacts. In this study, a computational algorithm called FFPEsig is introduced to rectify these artifacts and enable accurate mutational signature analysis.
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.

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