Enabling whole genome sequencing analysis from FFPE specimens in clinical oncology
The adoption of whole genome sequencing (WGS) in clinical oncology is challenged by low data quality and increased artifacts in standard-of-care formalin-fixed paraffin-embedded (FFPE) samples. Analysis of 56 fresh frozen (FF) and FFPE matched pairs demonstrates that FFPE processing results in a median 20-fold enrichment in artifactual calls across mutation classes and impairs detection of clinically relevant biomarkers such as homologous recombination deficiency (HRD). We demonstrate that implementation of consensus calling reduces artifactual structural variant (SV) calls by 98% but is not sufficient in mitigating artifactual calls for single nucleotide variants (SNVs) and indels as compared to FF data. We develop FFPErase, a machine learning framework that filters SNV/indel artifacts and delivers clinical grade variant reporting allowing accurate quantification of clinically relevant biomarkers. Comparison of FFPErase WGS calls to clinical reporting by FDA-approved panel tests demonstrates 99% sensitivity and enables reporting of 24% more clinically relevant findings.
Authors
- Pauline Robbe (ORCID: https://orcid.org/0000-0002-0691-1126)
- Max F. Levine (ORCID: https://orcid.org/0000-0001-5156-9086)
- Georgios Asimomitis (ORCID: https://orcid.org/0000-0002-9479-5451)
- Neerav Narendra Shukla (ORCID: https://orcid.org/0000-0003-2516-2965)
- Charlotte Brierley (ORCID: https://orcid.org/0000-0002-4028-3733)
- Neeman Mohibullah
- Sohrab P. Shah (ORCID: https://orcid.org/0000-0001-6402-523X)
- Tara J. O’Donohue (ORCID: https://orcid.org/0000-0001-9814-0690)
- Britta Weigelt (ORCID: https://orcid.org/0000-0001-9927-1270)
- Andrew McPherson (ORCID: https://orcid.org/0000-0002-5654-5101)
- Joachim Silber
- Dawn R. Cochrane
- Andrew L. Kung (ORCID: https://orcid.org/0000-0002-9091-488X)
- Anna Schuh (ORCID: https://orcid.org/0000-0002-3938-8490)
- Juan Arango Ossa (ORCID: https://orcid.org/0000-0003-1109-6178)
- Oliver Zivanovic (ORCID: https://orcid.org/0000-0003-1305-4991)
- Dylan Domenico (ORCID: https://orcid.org/0000-0002-6041-5078)
- Elli Papaemmanuil (ORCID: https://orcid.org/0000-0003-1709-8983)
- Janine Senz (ORCID: https://orcid.org/0009-0007-5475-4974)
- Gunes Gundem (ORCID: https://orcid.org/0000-0002-0070-9859)
- Cassidy C. Cobbs (ORCID: https://orcid.org/0000-0003-4465-8894)
- Emily Stockfisch (ORCID: https://orcid.org/0000-0002-4700-8937)
- Umesh Bhanot (ORCID: https://orcid.org/0000-0001-6656-1239)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Oxford (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Molecular Oncology (United States) (US)
- RIKEN Center for Integrative Medical Sciences (JP)
- Igenbio (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1038/s41467-025-65654-7
- Citations
- 1
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- Memorial Sloan-Kettering Cancer Center
- Geoffrey Beene Foundation
- National Institutes of Health
- National Cancer Institute