Large-scale analysis of whole genome sequencing data from formalin-fixed paraffin-embedded cancer specimens demonstrates preservation of clinical utility

Shadi Basyuni, Laura Heskin, Andrea Degasperi, Daniella Black, Gene C. C. Koh, Lucia Chmelova, Giuseppe Rinaldi, Steven Bell, Louise Grybowicz, Greg Elgar, Yasin Memari, Pauline Robbe, Zoya Kingsbury, Carlos Caldas, Jean Abraham, Anna Schuh, Louise Jones, Marc Tischkowitz, Matthew A. Brown, Helen R. Davies and Serena Nik-Zainal ()
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Shadi Basyuni: University of Cambridge
Laura Heskin: University of Cambridge
Andrea Degasperi: University of Cambridge
Daniella Black: University of Cambridge
Gene C. C. Koh: University of Cambridge
Lucia Chmelova: University of Cambridge
Giuseppe Rinaldi: University of Cambridge
Steven Bell: University of Cambridge
Louise Grybowicz: Cambridge University Hospitals
Greg Elgar: One Canada Square
Yasin Memari: University of Cambridge
Pauline Robbe: University of Oxford
Zoya Kingsbury: Illumina Centre
Carlos Caldas: Li Ka Shing Centre
Jean Abraham: University of Cambridge
Anna Schuh: University of Oxford
Louise Jones: Charterhouse Square
Marc Tischkowitz: University of Cambridge
Matthew A. Brown: University of Oxford
Helen R. Davies: University of Cambridge
Serena Nik-Zainal: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Whole genome sequencing (WGS) provides comprehensive, individualised cancer genomic information. However, routine tumour biopsies are formalin-fixed and paraffin-embedded (FFPE), damaging DNA, historically limiting their use in WGS. Here we analyse FFPE cancer WGS datasets from England’s 100,000 Genomes Project, comparing 578 FFPE samples with 11,014 fresh frozen (FF) samples across multiple tumour types. We use an approach that characterises rather than discards artefacts. We identify three artefactual signatures, including one known (SBS57) and two previously uncharacterised (SBS FFPE, ID FFPE), and develop an “FFPEImpact” score that quantifies sample artefacts. Despite inferior sequencing quality, FFPE-derived data identifies clinically-actionable variants, mutational signatures and permits algorithmic stratification. Matched FF/FFPE validation cohorts shows good concordance while acknowledging SBS, ID and copy-number artefacts. While FF-derived WGS data remains the gold standard, FFPE-samples can be used for WGS if required, using analytical advancements developed here, potentially democratising whole cancer genomics to many.

Date: 2024
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DOI: 10.1038/s41467-024-51577-2

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