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; PARTNER Trial Group; Personalised Breast Cancer Program Group; Marc Tischkowitz; Matthew A Brown; Helen R Davies; Serena Nik-Zainal

doi:10.1038/s41467-024-51577-2

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

Nat Commun. 2024 Sep 4;15(1):7731. doi: 10.1038/s41467-024-51577-2.

Authors

Shadi Basyuni^#^{1

2}, Laura Heskin^#^{1

2}, Andrea Degasperi^{1

2}, Daniella Black^{1

2}, Gene C C Koh^{1

2}, Lucia Chmelova^{1

2}, Giuseppe Rinaldi^{1

2}, Steven Bell^{3

4}, Louise Grybowicz⁵, Greg Elgar⁶, Yasin Memari^{1

2}, Pauline Robbe^{7

8}, Zoya Kingsbury⁹, Carlos Caldas⁴, Jean Abraham^{3

4}, Anna Schuh⁷, Louise Jones¹⁰; PARTNER Trial Group; Personalised Breast Cancer Program Group; Marc Tischkowitz¹, Matthew A Brown⁷, Helen R Davies^{1

2}, Serena Nik-Zainal^{11

12}

Affiliations

¹ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
² Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK.
³ Precision Breast Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴ Cancer Research UK Cambridge Centre, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
⁵ Cambridge Cancer Trials Centre, Department of Oncology, Cambridge University Hospitals, Cambridge, UK.
⁶ Genomics England, One Canada Square, London, UK.
⁷ Department of Oncology, University of Oxford, Oxford, UK.
⁸ RIKEN Centre for Integrative Medical Sciences, Yokohama, Japan.
⁹ Illumina Cambridge, Ltd, Illumina Centre, Cambridge, UK.
¹⁰ Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK.
¹¹ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK. sn206@cam.ac.uk.
¹² Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK. sn206@cam.ac.uk.

^# Contributed equally.

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.

MeSH terms

Artifacts
Formaldehyde*
Genome, Human
Genomics / methods
Humans
Mutation
Neoplasms* / genetics
Neoplasms* / pathology
Paraffin Embedding* / methods
Tissue Fixation* / methods
Whole Genome Sequencing* / methods

Substances

Formaldehyde

Grants and funding

WT_/Wellcome Trust/United Kingdom