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

Author

Listed:
  • Shadi Basyuni

    (University of Cambridge
    University of Cambridge)

  • Laura Heskin

    (University of Cambridge
    University of Cambridge)

  • Andrea Degasperi

    (University of Cambridge
    University of Cambridge)

  • Daniella Black

    (University of Cambridge
    University of Cambridge)

  • Gene C. C. Koh

    (University of Cambridge
    University of Cambridge)

  • Lucia Chmelova

    (University of Cambridge
    University of Cambridge)

  • Giuseppe Rinaldi

    (University of Cambridge
    University of Cambridge)

  • Steven Bell

    (University of Cambridge
    Li Ka Shing Centre)

  • Louise Grybowicz

    (Cambridge University Hospitals)

  • Greg Elgar

    (One Canada Square)

  • Yasin Memari

    (University of Cambridge
    University of Cambridge)

  • Pauline Robbe

    (University of Oxford
    RIKEN Centre for Integrative Medical Sciences)

  • Zoya Kingsbury

    (Illumina Centre)

  • Carlos Caldas

    (Li Ka Shing Centre)

  • Jean Abraham

    (University of Cambridge
    Li Ka Shing Centre)

  • 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
    University of Cambridge)

  • Serena Nik-Zainal

    (University of Cambridge
    University of Cambridge)

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.

Suggested Citation

  • 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 & Zoy, 2024. "Large-scale analysis of whole genome sequencing data from formalin-fixed paraffin-embedded cancer specimens demonstrates preservation of clinical utility," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51577-2
    DOI: 10.1038/s41467-024-51577-2
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    References listed on IDEAS

    as
    1. Serena Nik-Zainal & Helen Davies & Johan Staaf & Manasa Ramakrishna & Dominik Glodzik & Xueqing Zou & Inigo Martincorena & Ludmil B. Alexandrov & Sancha Martin & David C. Wedge & Peter Van Loo & Young, 2016. "Landscape of somatic mutations in 560 breast cancer whole-genome sequences," Nature, Nature, vol. 534(7605), pages 47-54, June.
    2. Jean E. Abraham & Karen Pinilla & Alimu Dayimu & Louise Grybowicz & Nikolaos Demiris & Caron Harvey & Lynsey M. Drewett & Rebecca Lucey & Alexander Fulton & Anne N. Roberts & Joanna R. Worley & Anita , 2024. "The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer," Nature, Nature, vol. 629(8014), pages 1142-1148, May.
    3. Ludmil B. Alexandrov & Jaegil Kim & Nicholas J. Haradhvala & Mi Ni Huang & Alvin Wei Tian Ng & Yang Wu & Arnoud Boot & Kyle R. Covington & Dmitry A. Gordenin & Erik N. Bergstrom & S. M. Ashiqul Islam , 2020. "The repertoire of mutational signatures in human cancer," Nature, Nature, vol. 578(7793), pages 94-101, February.
    Full references (including those not matched with items on IDEAS)

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